Pyridine Derivatives

ABSTRACT

The present application provides novel pyridine compounds and pharmaceutically acceptable salts or prodrugs thereof. Also provided are methods for preparing these compounds. These compounds are useful in inhibiting CYP17 activity by administering a therapeutically effective amount of one or more of the compounds to a patient. By doing so, these compounds are effective in treating conditions associated with CPY17 activity. A variety of conditions can be treated using these compounds and include diseases which are characterized by abnormal cellular proliferation. In one embodiment, the disease is cancer, such as prostate cancer.

BACKGROUND

Prostate cancer is the most common malignancy for older men and is amajor cause of death for that population. Until recently, it wasbelieved that reduction of testosterone was a key component in treatingpatients diagnosed with prostate cancer. However, a large number ofpatients having prostate cancer do not respond to reduction oftestosterone levels instigated by luteinizing hormone releasing hormone(LHRH) agonists and were thereby dubbed as having “hormone resistant”cancer. Only half of these patients having “hormone-resistant” prostatecancer respond to hormonal treatments.

It is currently recognized that LHRH agonists or antagonists do notcompletely reduce circulating testosterone levels due to sources otherthan the testes that can synthesize testosterone, including the adrenalgland and the prostate tumors themselves. The cytochrome P450 (CYP)enzymes include a large family of highly conserved enzymes, includingCYP17, that are involved in the synthesis of cholesterol and otherbioactive steroids. The fact that these enzymes are involved in steroidhormone biosynthesis has led to recent findings thatcastration-resistant prostate cancer in men and certain breast cancersin women are responsive to CYP17 inhibition.

CYP17 is a key enzyme in the production of androgenic steroids in manytissues, including prostate tumors, and catalyzes the 17α-hydroxylasereaction and 17,20-lyase reaction of both progesterone and pregnenolone.Inhibition of CYP17 results in reducing the levels ofdehydroepiandrostenedione (DHEA) and androstenedione, which are weakandrogens and precursors that are subsequently converted to testosteroneand dihydrotestosterone by other enzymes.

Designing inhibitors of CYP17 is problematic for several reasons. First,there is limited information regarding the structure of this enzyme.Second, human CYP17 is not available from natural sources, therebyrequiring its recombinant generation. Ketoconazole has been used toinhibit CYP17, but is not very potent and is non-selective since itinhibits other CYP enzymes. Other CYP17 inhibitors have been reported,and the steroidal CYP17 inhibitor Zytiga™ (abiraterone acetate) wasrecently approved by the U.S. Food and Drug Administration (FDA) for usein combination with prednisone for the treatment of patients withmetastatic castration-resistant prostate cancer (CRPC) who have receivedprior chemotherapy containing docetaxel. Most CYP17 inhibitors, however,including both steroidal compounds such as abiraterone and non-steroidalcompounds, have limited selectivity for CYP17, short in vivo half-lives,and/or poor bioavailability.

What is needed are alternative medications for treating prostate andother cancers that function by inhibiting CYP17.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound of formula (I),wherein A, B and R¹ are defined herein, or a pharmaceutically acceptablesalt or prodrug thereof

In another aspect, the invention provides a pharmaceutical compositioncontaining a compound of formula (I) and a pharmaceutically acceptablecarrier.

In a further aspect, the invention provides a method for regulatingCYP17 by administering a therapeutically effective amount of a compoundof formula (I) to a patient in need thereof.

In another aspect, the invention provides a method for inhibiting CYP17activity by administering a therapeutically effective amount of acompound of formula (I) to a patient in need thereof.

In yet another aspect, methods for treating conditions treatable byinhibiting CYP17 activity are provided and include administering acompound of formula (I) to a patient in need thereof.

In a further aspect, methods for treating cancer, such as prostatecancer, are provided and include administering a compound of formula (I)to a patient in need thereof.

In a still further aspect, methods for reducing testosterone productionin a patient by administering a therapeutically effective amount of acompound of formula (I) to a patient in need thereof.

Other aspects and advantages of the invention will be readily apparentfrom the following detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides compounds and pharmaceutical composition thereof,which are useful for regulating CYP17 activity and are, therefore,capable of treating conditions associated with abnormal cellproliferation. Specifically, the inventors found that it was the linkingof the pyridine ring to a phenyl-heteroaryl or bi-heteroaryl group via ahydroxymethylene fragment or an aminomethylene fragment which providedcompounds that selectively inhibit CYP17.

The compounds discussed herein are encompassed by the followingstructure of formula (I):

In this structure, A is optionally substituted phenyl or optionallysubstituted heteroaryl.

-   -   a. In one embodiment, A is

-   -    wherein R², R³, R⁴, R⁵, and R⁶ are, independently, selected        from among H, halogen, OH, CN, optionally substituted C₁ to C₆        alkyl, C₁ to C₆ alkoxy, H₂NC(O)—, (C₁ to C₄ alkyl)-NHC(O)—, (C₁        to C₄ alkyl)₂NC(O)—, HC(O)NH—, (C₁ to C₄ alkyl)-C(O)NH—, COOH,        C₁ to C₆ alkylsulfonyl and —C(O)O(C₁ to C₄ alkyl). 3, 4 or 5 of        R², R³, R⁴, R⁵, and R⁶ are hydrogen.    -   b. In another embodiment, A is

-   -   c. In a further embodiment, A is

-   -   d. In another embodiment, A is optionally substituted pyridine.    -   e. In still a further embodiment, A is

-   -    In these structures, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are,        independently, selected from among H, halogen, OH, CN,        optionally substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy,        H₂NC(O)—, (C₁ to C₄ alkyl)-NHC(O)—, (C₁ to C₄ alkyl)₂NC(O)—,        HC(O)NH—, (C₁ to C₄ alkyl)-C(O)NH—, COOH, C₁ to C₆ alkylsulfonyl        and —C(O)O(C₁ to C₄ alkyl). 2, 3 or 4 of R⁷, R⁸, R⁹, R¹⁰, and        R¹¹ are hydrogen.    -   f. In still another embodiment, A is

-   -   g. In yet a further embodiment, A is optionally substituted        pyridone.    -   h. In another embodiment, A is

-   -    In this structure, R⁷, R⁸, R¹⁰ and R¹¹ are, independently,        selected from among H, halogen, OH, CN, optionally substituted        C₁ to C₆ alkyl, C₁ to C₆ alkoxy, H₂NC(O)—, (C₁ to C₄        alkyl)-NHC(O)—, (C₁ to C₄ alkyl)₂NC(O)—, HC(O)NH—, (C₁ to C₄        alkyl)-C(O)NH—, COOH, C₁ to C₆ alkylsulfonyl and —C(O)O(C₁ to C₄        alkyl).    -   i. In still a further embodiment, A is

-   -    In one example, R¹⁰ is C₁ to C₆ alkyl.    -   j. In yet another embodiment, A is

-   -    In this structure, R¹³ and R¹⁴ are, independently, selected        from among H, halogen, OH, CN, optionally substituted C₁ to C₆        alkyl, C₁ to C₆ alkoxy, H₂NC(O)—, (C₁ to C₄ alkyl)-NHC(O)—, (C₁        to C₄ alkyl)₂NC(O)—, HC(O)NH—, (C₁ to C₄ alkyl)-C(O)NH—, COOH,        C₁ to C₆ alkylsulfonyl and —C(O)O(C₁ to C₄ alkyl); and R¹⁵ is H        or C₁ to C₆ alkyl.    -   k. In a further embodiment, A is

-   -    In one example, R¹⁵ is H.        -   In formula (I), B is an optionally substituted heteroaryl.        -   i. In one embodiment, B is an optionally substituted            pyridine.        -   ii. In another embodiment, B is

-   -   -   In these structures for B, R²⁰, R²¹ and R²² are            independently selected from among H, F, Cl, CH₃, CF₃, and            CN.        -   iii. In a further embodiment, B is

-   -   -    In one example, R²⁰, R²¹, and R²² are H.        -   iv. In yet another embodiment, B is

-   -   -    In these structures, X and Y are independently selected            from among CR²³ and N; Z is NR²⁴, O or S. Each R²³ is,            independently, H, F, Cl, CH₃, CF₃ or CN and R²⁴ is H or C₁            to C₄ alkyl.        -   v. In still a further embodiment, B is

-   -   -   vi. In yet another embodiment, B is

-   -   -   vii. In a further embodiment, B is

-   -   -   viii. In yet another embodiment, B is

-   -   -   ix. In still a further embodiment, B is

-   -   -   x. In still another embodiment, B is

-   -   -   xi. In yet a further embodiment, B is

In another embodiment, B is

In the structure of formula (I), R¹ is H or C₁ to C₄ alkyl. In anotherembodiment, R¹ is two or three methylene fragments, which are joined toa carbon atom at the 3-position of the pyridine ring. Further, Q is O orNH.

In another embodiment, the compounds discussed herein are encompassed bythe following structure of formula (I-A), wherein A, B, and R¹ aredefined herein.

In a further embodiment, the compounds discussed herein are encompassedby the following structure of formula (I-B), wherein A, B, and R¹ aredefined herein.

In still another embodiment, the compounds discussed herein areencompassed by the following structure of formula (I-D), wherein A, B,and R¹ are defined herein and R^(z) is C₁ to C₆ alkyl.

In yet a further embodiment, the compounds discussed herein areencompassed by the following structure of formula (I-E), wherein A, B,and R¹ are defined herein and R^(z) is C₁ to C₆ alkyl.

One of skill in the art would readily be able to select the A, B, and R¹groups with the knowledge that stable chemical bonds must be formed.Specifically, one of skill in the art would readily understand whichchemical bonds could/could not be formed and how to tailor the reactionsin view thereof. The term “stable” as used in this context, refers to aresultant molecule that can be prepared and isolated withoutdegradation.

Some compounds within the present invention possess one or more chiralcenters, and the present invention includes each separate enantiomer ofsuch compounds as well as mixtures of the enantiomers. Where multiplechiral centers exist in compounds of the present invention, theinvention includes each possible combination of chiral centers within acompound, as well as all possible enantiomeric and diastereomericmixtures thereof. All chiral, diastereomeric, and racemic forms of astructure are intended, unless the specific stereochemistry or isomericform is specifically indicated. It is well known in the art how toprepare optically active forms, such as by resolution of racemic formsor by synthesis from optically active starting materials.

The following definitions are used in connection with the compounds ofthe present invention unless the context indicates otherwise. Ingeneral, the number of carbon atoms present in a given group isdesignated “C_(x)-C_(y)”, where x and y are the lower and upper limits,respectively. For example, a group designated as “C₁-C₆” contains from 1to 6 carbon atoms. The carbon number as used in the definitions hereinrefers to carbon backbone and carbon branching, but does not includecarbon atoms of the substituents, such as alkoxy substitutions and thelike. Unless indicated otherwise, the nomenclature of substituents thatare not explicitly defined herein are arrived at by naming from left toright the terminal portion of the functionality followed by the adjacentfunctionality toward the point of attachment. The structures that arerepresented here are drawn without any stereochemical indication. It isimplied that when a chiral center is present in a molecule, it representboth enantiomers. Terms not defined herein have the meaning commonlyattributed to them by those skilled in the art.

“Alkyl” refers to a hydrocarbon chain that may be straight or branched,or to a hydrocarbon group that consists of or contains a cyclic alkylradical. In one embodiment, an alkyl contains 1 to 8 (inclusive) carbonatoms or integers or ranges there between. In another embodiment, analkyl contains 1 to 7 (inclusive) carbon atoms or ranges there between.In a further embodiment, an alkyl contains 1 to 6 (inclusive) carbonatoms. In yet another embodiment, an alkyl contains 1 to 5 (inclusive)carbon atoms. In still a further embodiment, an alkyl contains 1 to 4(inclusive) carbon atoms. Examples of alkyl groups that are hydrocarbonchains include, but are not limited to, methyl, ethyl, propyl, butyl,pentyl, hexyl, and heptyl, where all isomers of these examples arecontemplated. Examples of alkyl groups that consist of or contain acyclic alkyl radical include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, 3,3-dimethylcyclobutyl, (cyclopropyl)methyl,and (cyclopentyl)methyl.

“Optionally substituted alkyl” refers to an alkyl group, as definedabove, that is unsubstituted or substituted with one or more F, one ortwo Cl, one or two OH, one amino group, one (alkyl)amino group (i.e.,alkyl-NH—), one (dialkyl)amino group (i.e., (alkyl)₂N—), one or twoalkoxy groups, or one cyano group, or any combination of thesesubstituents. “Substituted” means that one or more of the alkyl group'shydrogen atoms is replaced with a substituent group as listed above.

“Alkoxy” refers to the group R—O— where R is an alkyl group, as definedabove. Exemplary C₁-C₆ alkoxy groups include but are not limited tomethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and t-butoxy.

“(Alkoxy)carbonyl-” refers to the group alkyl-O—C(O)—. Exemplary (C₁-C₆alkoxy)carbonyl groups include, but are not limited to, methoxy, ethoxy,n-propoxy, l-propoxy, n-butoxy and t-butoxy.

“(Alkyl)amido-” refers to the group —C(O)NH-alkyl. Representativeexamples of (C₁-C₆ alkyl)amido include, but are not limited to,—C(O)NHCH₃, —C(O)NHCH₂CH₃, —C(O)NHCH₂CH₂CH₃, —C(O)NHCH₂CH₂CH₂CH₃,—C(O)NHCH₂CH₂CH₂CH₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂,—C(O)NHCH(CH₃)CH₂CH₃, —C(O)NH—C(CH₃)₃ and —C(O)NHCH₂C(CH₃)₃.

“Di(alkyl)amido-” refers to a —C(O)—N group in which the nitrogen atomof the group is attached, independently, to alkyl groups, as definedabove. Each alkyl group can be independently selected. Representativeexamples of (C₁-C₆ alkyl)₂amido include, but are not limited to,—C(O)N(CH₃)₂, —C(O)N(CH₂CH₃)₂, —C(O)N(CH₂CH₂CH₃)₂,—C(O)N(CH₂CH₂CH₂CH₃)₂, —C(O)N(CH₂CH₂CH₂CH₂CH₃)₂, —C(O)N(CH₃)(CH₂CH₃),and —C(O)N(CH₂CH₃)(CH₂CH₂CH₃)₂.

“Alkylsulfonyl” refers to an alkyl-S(O)₂— group. Representative examplesof (C₁-C₆ alkyl)sulfonyl group are, but are not limited to, CH₃S(O)₂—and CH₃CH₂S(O)₂—.

“(Alkyl)amino-” refers to an alkyl-NH— group. Representative examples of(C₁-C₆ alkyl)amino group are, but are not limited to, CH₃NH—, CH₃CH₂NH—,CH₃CH₂CH₂NH—, CH₃CH₂CH₂CH₂NH—, (CH₃)₂CHNH—, (CH₃)₂CHCH₂NH—,CH₃CH₂CH(CH₃)NH— and (CH₃)₃CNH—.

“(Dialkyl)amino-” refers to an (alkyl)₂N— group, wherein the two alkylgroups are independently selected. Representative examples of di(C₁-C₆alkyl)amino include, but are not limited to (CH₃)₂N—, (CH₃CH₂)₂N—,(CH₃CH₂CH₂)₂N—, (CH₃)(CH₂CH₃)N—, (CH₃)(CH₂CH₂CH₃)N—, and(CH₃CH₂)(CH₂CH₂CH₃)N—.

“Alkylcarboxy-” refers to an alkyl group, defined above that is attachedto the parent structure through the carbon atom of a carboxy (C(O)—O—)functionality. Examples of (C₁-C₆ alkyl)carboxy include acetoxy,propionoxy, propylcarboxy, and isopentylcarboxy.

“(Alkyl)carboxamido-” refers to a —NHC(O)-alkyl- group in which thecarbonyl carbon atoms of the group is attached to an alkyl group.Representative examples of (C₁-C₆ alkyl)carboxamido include, but are notlimited to, —NHC(O)CH₃, N(CH₃)C(O)CH₃, —N(CH₃)C(O)CH₂CH₃,—N(CH₃)C(O)CH₂CH₂CH₃, —N(CH₃)C(O)CH₂CH₂CH₂CH₃,—N(CH₂CH₃)C(O)CH₂CH₂CH₂CH₂CH₃, —N(CH₂CH₃)C(O)CH(CH₃)₂,—N(CH₂CH₃)C(O)CH₂CH(CH₃)₂, —N(CH₂CH₃)C(O)CH(CH₃)CH₂CH₃, and—N(CH₂CH₃)C(O)C(CH₃)₃.

“Optionally substituted phenyl” refers to a phenyl group that can beunsubstituted or substituted with one or more of optionally substitutedalkyl, halogen, OH, NH₂, alkylamino-, di(alkyl)amino-, cyano, COOH,(alkoxy)carbonyl-, alkylcarboxy-, (alkyl)carboxamido-, alkylsulfonyl,—C(O)NH₂, (alkyl)amido-, di(alkyl)amido-, NO₂, or alkoxy.

“Halo” or “halogen” refers to F, Cl, Br and I.

“Heteroaryl” refers to a monocyclic 5-membered or 6-membered aromaticring system containing at least one ring atom selected from theheteroatoms oxygen, sulfur and nitrogen. Examples of heteroaryl groupsinclude furan, thiophene, indole, azaindole, oxazole, thiazole,isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine,pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole,N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole,1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, and pyridone,including 2-pyridone.

“Optionally substituted heteroaryl” refers to a heteroaryl group, asdefined above, that is unsubstituted or substituted with one or more ofoptionally substituted alkyl, F, Cl, OH, NH₂, alkylamino-,di(alkyl)amino-, cyano, COOH, (alkoxy)carbonyl-, alkylcarboxy-,(alkyl)carboxamido-, alkylsulfonyl, —C(O)NH₂, (alkyl)amido-,di(alkyl)amido-, NO₂, or alkoxy.

A “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog,cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or gorilla.

Representative “pharmaceutically acceptable salts” include but are notlimited to, e.g., water-soluble and water-insoluble salts, includingsalts of acids. Examples of acids which can form salts with thecompounds discussed herein include, without limitation, acetic,propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic,mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric,nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic,toluenesulfonic, trifluoroacetic, and camphorsulfonic.

In a further embodiment, a compound of the invention may be a solvate.As used herein, a solvate does not significantly alter the physiologicalactivity or toxicity of the compounds, and as such may function aspharmacological equivalents to non-solvate compounds of the invention.The term “solvate” as used herein is a combination, physical associationand/or solvation of a compound of the present invention with a solventmolecule. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instances,the solvate can be isolated, such as when one or more solvent moleculesare incorporated into the crystal lattice of a crystalline solid. Thus,“solvate” encompasses both solution-phase and isolatable solvates.

In a further embodiment, a compound of the invention may be a prodrug ofa compound of formula (I). Prodrugs of compounds of formula (I) may beprepared and used as a means to modulate the pharmacokinetic properties,using various methods known to those skilled in the art. See, e.g.,Rautio, Nature Reviews Drug Discovery, 7:255-270 (2008) and Ettmayer, J.Med. Chem., 47:2393-2404 (2004), which are hereby incorporated byreference. In the case of drugs containing a hydroxy moiety, acetyl andother ester analogs are contemplated for use as prodrugs. See, e.g.,Beaumont, Current Drug Metabolism, 4:461-485 (2003), which is herebyincorporated by reference. In the case of drugs containing an aminemoiety, prodrugs containing amides and carbamates are contemplated. See,e.g., Simplicio, Molecules, 13:519-547 (2008), which is herebyincorporated by reference. As specific examples,(alkoxycarbonyloxy)alkyl carbamates, (acyloxy)alkyl carbamates, and(oxodioxolenyl)alkyl carbamates may be utilized as effective prodrugstrategies for amines See, e.g., Li, Bioorg. Med. Chem. Lett.,7:2909-2912 (1997); Alexander, J. Med. Chem., 34:78-81 (1991);Alexander, J. Med. Chem., 31:318-322 (1988); and Alexander, J. Med.Chem., 39:480-486 (1996), all of which are incorporated by referenceherein.

Some compounds within the present invention possess one or more chiralcenters, and the present invention includes each separate enantiomer ofsuch compounds as well as mixtures of the enantiomers. Where multiplechiral centers exist in compounds of the present invention, theinvention includes each possible combination of chiral centers within acompound, as well as all possible enantiomeric mixtures thereof. Allchiral, diastereomeric, and racemic forms of a structure are intended,unless the specific stereochemistry or isomeric form is specificallyindicated. It is well known in the art how to prepare optically activeforms, such as by resolution of racemic forms or by synthesis fromoptically active starting materials.

The words “comprise”, “comprises”, and “comprising” are to beinterpreted inclusively rather than exclusively. The works “consist”,“consisting”, and its variants, are to be interpreted exclusively,rather than inclusively.

As used herein, the term “about” means a variability of 10% from thereference given, unless otherwise specified.

Processes for Preparing the Compounds

Methods useful for making the compounds of formula (I) are set forth inthe Examples below and generalized in the schemes. One of skill in theart will recognize that the schemes can be adapted to produce the othercompounds of formula (I) and pharmaceutically acceptable salts orprodrugs of compounds of formula (I).

In the following reactions described to prepare compounds describedherein, it can be necessary to protect reactive functional groups, forexample OH, amino, imino, thio or carboxy groups, where these aredesired in the final product, to avoid their unwanted participation inthe reactions. Conventional protecting groups can be used in accordancewith standard practices, for example, see T. W. Green and P. G. M. Wutsin “Protective Groups in Organic Chemistry”, John Wiley &Sons, 1991.

The following methods outline the synthesis of the compounds of formula(I). The following examples are presented to illustrate certainembodiments of the present invention, but should not be construed aslimiting the scope of the invention.

Scheme 1 depicts one synthesis method to prepare compounds of formula(I-A). In one embodiment, a boronic acid (R_(a)=H) or boronate ester(R_(a)=alkyl) derivative of fragment A [A] is first coupled to aheteroaryl halide [B], wherein X=halogen. In a further embodiment, [B]is a heteroaryl triflate, wherein X is trifluoromethylsulfonate. Thisreaction may be performed using, e.g., a boronic acid pinacol esterderivative [A], in the presence of a weak base and a palladium catalyst.In one embodiment, the weak base is KOAc or Na₂CO₃. In anotherembodiment, the palladium catalyst is Pd(PPh₃)₄, Pd(dppf)Cl₂.DCM orPd(dppf)Cl₂. In a further embodiment, the reaction is performed in asolvent such as toluene/ethanol, 1,4-dioxane or DMF. In yet anotherembodiment, the reaction is performed at elevated temperatures up to thereflux temperature of the solvent. The intermediate [C] is then reactedwith the 4-anion of pyridine, i.e., M-pyridine shown in Scheme 1,wherein M is a metal or metalloid moiety such as Li, Mg—Br or Mg—Cl. Inone embodiment, the 4-anion of pyridine is pyridin-4-yl lithium, whichmay be generated from 4-iodo-pyridine or 4-bromo-pyridine upon treatmentwith an alkyl metal reagent such as n-butyl lithium.

Scheme 2 provides a method wherein compounds of formula (I) can beprepared, by first preparing aldehyde intermediate [C] by the methodindicated in Scheme 1, followed by a two-step conversion to an alkylketone [C] (R¹=C₁ to C₄ alkyl). Ketone [C] (R¹=C₁ to C₄ alkyl) is thenconverted to compounds of formula (I) by the method described inScheme 1. In one embodiment, aldehyde [C] is reacted with an alkyl metalreagent to produce hydroxy intermediate [D]. In another embodiment, thealkyl metal reagent is an alkyl lithium or alkyl Grignard reagent(alkyl-MgX). Intermediate [D] is oxidized with an oxidizing agent toproduce the alkyl ketone [C] (R¹=C₁ to C₄ alkyl). In one embodiment, theoxidizing agent is Dess-Martin periodinane. In a further embodiment, theoxidizing agent is MnO₂ or PCC (pyridinium chlorochromate). Ketone [C](equivalent to intermediate [C] in Scheme 1) may then be converted tocompounds of formula (I) by the method described herein such as inScheme 1.

Scheme 2A applies the two-step methodology as described in Scheme 2 toconvert compounds of Formula (I-A), where R¹=H, via the ketoneintermediate [E], into compounds of formula (I), where R¹=C₁ to C₄alkyl.

Scheme 3 depicts a further method for the preparation of compounds offormula (I-A). In one embodiment, a boronic acid (R_(a)=H) or boronateester (R_(a)=alkyl) derivative of fragment A [A] is first coupled to aheteroaryl halide [F], where X=halogen, to produce intermediate [G]. Ina further embodiment, [F] is a heteroaryl triflate, wherein X istrifluoromethylsulfonate. This coupling reaction may be performed using,e.g., a boronic acid pinacol ester derivative [A], a weak base, and apalladium catalyst. In one embodiment, the weak base is KOAc or Na₂CO₃.In another embodiment, the palladium catalyst is Pd(PPh₃)₄,Pd(dppf)Cl₂.DCM or Pd(dppf)Cl₂. Desirably the reaction is performed in asolvent such as toluene/ethanol, 1,4-dioxane or DMF. The reaction may beperformed at elevated temperatures up to the reflux temperature of thesolvent. An anionic species of [G] is then generated from [G] bytreatment with a strongly basic reagent. In one embodiment, the stronglybasic reagent is n-butyl lithium or lithium diisopropylamide (LDA). Thisanionic species is then reacted with a pyridin-4-yl alkyl ketone [H] toform compounds of formula (I-A).

Scheme 4 describes a further method for the synthesis of compounds offormula (I-A). In this method, a boronic acid (R_(a)=H) or boronateester (R_(a)=alkyl) derivative of fragment A [A] is first coupled to aheteroaryl di-halide [J], wherein X is, independently, halogen, toproduce intermediate [K]. This coupling reaction may be performed by themethod described for Scheme 1. In one embodiment, an anionic species of[K] is then generated from [K] by treatment with an alkyl metal reagent.In one embodiment, the alkyl metal reagent is n-butyl lithium. In afurther embodiment, the anionic species of [K] is a Grignard reagent,generated from [K] by treatment with magnesium. The anionic species of[K] is then reacted with a pyridin-4-yl alkyl ketone [H] to formcompounds of formula (I-A).

Scheme 5 depicts a further method for the preparation of compounds offormula (I-A). In this scheme, methods as described in Scheme 3 are usedto prepare intermediate [G]. An anionic species of [G] is then generatedfrom [G] by treatment with a strongly basic reagent. In one embodiment,the strongly basic reagent is n-butyl lithium or lithiumdiisopropylamide (LDA). This anionic species is then reacted with DMF toform aldehyde intermediate [C]. Aldehyde [C] is then converted in twosteps to produce alkyl ketone [C] (R¹=C₁ to C₄ alkyl) by the methoddescribed in Scheme 2. Ketone [C] (R¹=C₁ to C₄ alkyl) is then convertedto a compound of formula (I-A) by the method described in Scheme 1.Aldehyde intermediate [C] (R¹=H) may also be converted directly to acompound of formula (I-A) where R¹=H, by the methods described herein,such as Scheme 1.

Scheme 6 depicts another method that is used for the synthesis ofcompounds of formula (I-A). In this scheme, a halide [L], wherein X ishalogen, is coupled with a boronic acid (R_(a)=H) or boronate ester(R_(a)=alkyl) derivative of fragment B [N], using the methodologydescribed herein, such as for Scheme 1. The intermediate [C] is thenreacted with the 4-anion of pyridine, as described for Scheme 1, whereinM is a metal or metalloid moiety such as Li, Mg—Br or Mg—Cl. In oneembodiment, the 4-anion of pyridine is pyridin-4-yl lithium.

It will be apparent to those skilled in the art that there are a varietyof other known coupling reaction methods that can be used to produceintermediates such as compound [G] in Schemes 1, 2, and 4. For example,as depicted in Scheme 7, a halide [L], where X is halogen, can becoupled with a heteroaryl species [P]. In one embodiment, the couplingis performed in the presence of CuI. In another embodiment, the couplingis performed in the presence of a palladium catalyst such as Pd(OAc)₂.In a further embodiment, the reaction is carried out at an elevatedtemperature such as 140° C. In still another embodiment, the reaction isperformed in a solvent such as DMF. Alternatively, a halide [L] can becoupled with a heteroaryl species [P]. In one embodiment, this couplingis performed in the presence of AgF. In another embodiment, thiscoupling is performed in the presence of, PPh₃ and a palladium catalystsuch as Pd(PPh₃)₂Cl₂. The intermediate [G] that is produced may beconverted to compounds of formula (I-A) by the methods described herein,such as those for Scheme 3.

Scheme 8 describes a further coupling method that can be used in thepreparation of compounds of formula (I-A). In this method, a halide [L],wherein X is halogen, is reacted with an activated derivative of B [Q1].The intermediate [G] that is produced may be converted to compounds ofFormula (I-A) including reaction with pyridine compound [H] and by themethods described above, such as Scheme 3.

Scheme 8A describes one example of the general method of Scheme 8. Inthis embodiment, a halide [L], where X is halogen, is reacted with a tinderivative of B [Q2]. In one embodiment, the tin derivative is tributyltin derivative ([Q2] where R_(b)=butyl). In another embodiment, thecoupling reaction is carried out at elevated temperatures, such as 100°C. In a further embodiment, the coupling reaction is performed in asolvent, such as DMF. In still another embodiment, the coupling reactionis performed in the presence of a palladium catalyst, such asPd(PPh₃)₂Cl₂. The intermediate [G] that is produced may be converted tocompounds of Formula (I-A) by the methods described above, such asScheme 3.

Scheme 8B describes a second example of the general method of Scheme 8.In this embodiment, a halide [L], wherein X is a halogen, is reactedwith a boronic acid (R_(a)=H) or boronate ester (R_(a)=alkyl) derivativeof fragment B [R]. This coupling reaction is carried out using variousconditions, for example, as described for the related reaction step inScheme 3. The intermediate [G] that is produced can be converted tocompounds of Formula (I-A) by the methods described above, such asScheme 3.

Scheme 8C describes a third example of the general method of Scheme 8.In this embodiment, a halide [L], wherein X is halogen, is reacted witha zinc derivative of fragment B [S]. The zinc derivative [S] may beprepared by treating fragment B with an alkyl lithium such as n-butyllithium and zinc chloride, in THF at low temperatures such as −78° C.The coupling of [L] and [S] may be carried out in the presence of anickel catalyst or a palladium catalyst, such as Pd(PPh₃)₄. Theintermediate [G] that is produced may be converted to compounds ofFormula (I-A) by the methods described above, such as Scheme 3.

It will be recognized by those skilled in the art that various othermethods can be used to prepare compounds of formula (I-A), in whicheither fragment A or B are produced by a cyclization reaction. See,Scheme 9. In this scheme, the 1,3,4-thiadiazole ring is prepared byreacting hydrazine carbothiamide with ethyloxalyl chloride in thepresence of a cyclizing agent. In one embodiment, the cyclizing agent isPOCl₃ or P₂O₅. In another embodiment, the cyclization is performed atelevated temperatures. The amine group bound to the thiadiazole ring ofthe intermediate is then replaced with a bromine substituent. In oneembodiment, the reaction is performed using cupric bromide in thepresent of t-butyl nitrite. In another example, the reaction isperformed at about 0° C. to about 60° C. in acetonitrile. The estersubstituent is then reduced to the corresponding alcohol. In oneembodiment, the reduction is performed using reducing agents known inthe art such as sodium borohydride, lithium aluminum hydride, ordiisobutyl aluminum hydride. The resultant alcohol is then coupled withthe A substituent to provide intermediate [X]. In one embodiment, thecoupling is performed using a boronic acid or boronate ester derivativeof A, such as A-B(OH)₂. In another embodiment, the coupling is performedin the presence of a catalyst such as Pd(PPh₃)₄. Finally, intermediate[X] is oxidized to aldehyde [Y]. In one embodiment, the oxidation isperformed using Dess-Martin periodinane. In a further embodiment, theoxidation is performed by using MnO₂ or PCC (pyridinium chlorochromate).The methodology described herein, such as Schemes 1 and 2, may then beapplied to synthesize compounds of formula (I-A).

In another embodiment, compounds [Z] and [AA] may be prepared asdepicted in Scheme 9A. In this scheme, the steps are similar to thesteps of Scheme 9, with the exception that the “A” group of the boronicacid coupling reagent is a substituted phenyl group. In one embodiment,the “A” group of the boronic acid is 4-fluorophenyl and the product is5-(4-fluorophenyl)-1,3,4-thiadiazole-2-carbaldehyde [AA].

In a further embodiment, compounds of formula (I-A) may be preparedaccording to the transformations noted in Scheme 9B. In this scheme, thesteps and transformations parallel those recited in Schemes 9 and 9A.Specifically, the 1,3,4-thiadiazole ring is synthesized by reactinghydrazine carbothiamide with ethyloxalyl chloride in the presence ofPOCl₃. In one embodiment, the cyclization is performed at elevatedtemperatures of about 70° C. for about 3 hours. The intermediateproduced therefrom is then reacted with t-butyl nitrite in the presenceof cupric bromide. In one embodiment, the reaction is performed inacetonitrile as solvent. In another embodiment, the reaction isperformed at about room temperature to about 60° C. for about 1 hour.The resultant ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate is thenreduced using sodium borohydride. In one embodiment, the reaction isperformed in methanol at about room temperature for about 16 hours toprovide 2-bromo-1,3,4-thiadiazolyl-5-methanol. This product is thencoupled with 4-fluoro-phenyl boronic acid to provide(5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methanol [Z]. In oneembodiment, the coupling is performed in the presence of Pd(PPh₃)₄. Inanother embodiment, the reaction is performed in toluene at an elevatedtemperature of about 100° C. for about 1 hour.(5-(4-Fluorophenyl)-1,3,4-thiadiazol-2-yl)methanol is then converted to5-(4-fluorophenyl)-1,3,4-thiadiazole-2-carbaldehyde via reaction withDess-Martin periodinane. In one embodiment, this reaction is performedin the presence of dichloromethane. In another embodiment, the reactionis performed at about room temperature of about 3 hours.

Scheme 10 provides a route to intermediate [CC] and/or [DD] via acyclization reaction. In this case, a 1,2,4-oxadiazole ring is generatedduring the preparation of1-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethanol [CC]. Specifically,2-hydroxy-propionitrile is converted to N,2-dihydroxypropanimidamideusing hydroxylamine hydrochloride. The resultant compound is thencoupled with the “A” substituent. In one embodiment, the resultantcompound is reacted with an A-substituted acyl chloride [BB] to provideintermediate [CC]. Compound [CC] is then oxidized to provide ketone[DD]. In one embodiment, the oxidation is performed using Dess-Martinperiodinane. In a further embodiment, the oxidation is performed byusing MnO₂ or PCC (pyridinium chlorochromate). Intermediate [DD] maythen be converted to a compound of formula (I-A) by the methods noted inthe schemes, such as Scheme 1.

Scheme 10A provides the synthesis of a compound of formula (I-A),wherein B is a substituted phenyl group. The steps and transformationsin this scheme parallel those described in Scheme 10, with the exceptionthat “A” is 4-fluorophenyl. By doing so, intermediate [CC] is1-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethanol which may be oxidizedto ketone [DD], i.e.,1-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethanone, using the reagentsand steps described in Scheme 10A.1-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethanone may then convertedto a compound of formula (I-A) using the methods described above, suchas Scheme 1.

Scheme 10B describes the preparation of1-(5-(4-fluorophenyl)-1,2,4-oxadiazon-3-yl)ethanone. In one embodiment,a 1,2,4-oxadiazole ring is generated during the preparation of1-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethanol by first reacting2-hydroxy-propionitrile with hydroxylamine hydrochloride in the presenceof ethanol or other lower alkyl alcohol as solvent, and sodium hydroxideor potassium hydroxide. In one embodiment, this reaction is performed atelevated temperatures such as the reflux temperature of the solvent. Theresultant compound N,2-dihydroxypropanimidamide is then coupled with4-fluoro-phenyl-chloroformate to provide intermediate1-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethanol. In one embodiment,the coupling is performed in ethanol. In another embodiment, thecoupling is performed at a temperature of about 0 to about 85° C.1-(5-(4-Fluorophenyl)-1,2,4-oxadiazol-3-yl)ethanol is then oxidized tothe corresponding ketone using Dess-Martin periodinane. In oneembodiment, the oxidation is performed in methylene chloride. In anotherembodiment, the oxidation is performed at about 0° C. to about roomtemperature.

Intermediates [GG] and [HH] may also be prepared according to themethodology and reagents of Scheme 10C. A cyano-substituted “A” reagent[EE] is reacted with hydroxylamine hydrochloride to result in anN-hydroxy-imidamide derivative “A” of [FF]. This compound [FF] is thenreacted with 2-hydroxy-propionic acid in the presence of a couplingagent to provide intermediate [GG]. In one embodiment, the couplingagent is dicyclohexylcarbodiimide (DCC) orN-ethyl-N′-dimethylaminoethyl-carbodiimide (EDCI). Compound [GG] is thenoxidized to ketone intermediate [HH]. In one embodiment, the oxidationis performed using manganese dioxide, PCC (pyridinium chlorochromate) orDess-Martin periodinane.

In another embodiment, intermediate compoundsI-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethanol and1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethanone may be prepared asdescribed in Scheme 10D. In this route, 4-fluoro-benzonitrile is reactedwith hydroxylamine hydrochloride to provide4-fluoro-N-hydroxybenz-imidamide. In one embodiment, the reaction isperformed at refluxing temperatures. In another embodiment, the reactionis performed in the presence of a lower alkyl alcohol such as ethanol,and a base such as sodium hydroxide or potassium hydroxide. Theresultant compound is then reacted with 2-hydroxy-propionic acid toprovide 1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethanol. In oneembodiment, the reaction is performed in the presence of DMSO, DCC, andHOBt. 1-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)ethanol is thenoxidized to 1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethanone. In oneembodiment, the oxidation is performed using manganese dioxide indioxane.

A further example in which fragment B is produced by a cyclizationreaction is provided in Scheme 11. In this case, a 1,3,4-oxadiazolering, i.e., fragment B, is generated. Specifically, an A-substitutedethylformate [KK] is reacted with hydrazine hydrate to provide compound[LL]. Compound [LL] is then reacted with triethylorthoformate or boilingformic acid to provide intermediate [MM]. Compound [MM] may then beconverted to a compound of formula (I-A) by the methods described in theschemes, such as Scheme 3.

In one embodiment, 2-(4-fluorophenyl)-1,3,4-oxadiazole may be preparedas provided in Scheme 11A. In this case, 4-fluoro-phenyl-ethylformate isreacted with hydrazine hydrate to provide 4-fluorobenzohydrazide. Thisintermediate is then reacted with triethylorthoformate to provide2-(4-fluorophenyl)-1,3,4-oxadiazole. 2-(4-Fluorophenyl)-1,3,4-oxadiazolemay then be converted to a compound of formula (I-A) by the methodsdescribed herein.

In another embodiment, 2-(4-fluorophenyl)-1,3,4-oxadiazole is preparedaccording to the methodology and reagents of Scheme 11B. In thisembodiment, 4-fluoro-phenyl-ethylformate is reacted with hydrazinehydrate. In one embodiment, the reaction is performed in ethanol. Inanother embodiment, the reaction is performed at reflux temperatures forabout 10 hours. The resultant compound 4-fluorobenzohydrazide is thenreacted with triethylorthoformate to provide2-(4-fluorophenyl)-1,3,4-oxadiazole. In one embodiment, this reaction isperformed at about 140° C. for about 5 hours.

An additional example in which either intermediate [PP] or [QQ] areproduced by a cyclization reaction is provided in Scheme 12. In thisscheme, an A-substituted formaldehyde [NN] is reacted with hydroxylaminehydrochloride to provide an A-substituted oxime [OO]. Intermediate [OO]is then reacted with but-3-yn-2-ol and N-chlorosuccinimide (NCS) toprovide intermediate [PP], which is then oxidized to the correspondingketone [QQ]. In one embodiment, the oxidation is performed usingDess-Martin periodinane, manganese dioxide or PCC (pyridiniumchlorochromate). Intermediate [QQ] may then be converted to a compoundof formula (I-A) by the methods described in the schemes, such as Scheme1.

In another embodiment, 1-(3-(4-fluorophenyl)-isoxazol-5-yl)ethanol and1-(3-(4-fluorophenyl)-isoxazol-5-yl)ethanone may be produced asdescribed in Scheme 12A. 4-Fluoro-benzaldehyde is reacted withhydroxylamine hydrochloride to provide 4-fluorobenzaldehyde oxime. Theisoxazole ring is then generated by reacting this intermediate withbut-3-yn-2-ol and NCS to provide1-(3-(4-fluorophenyl)isoxazol-5-yl)ethanol.1-(3-(4-Fluorophenyl)isoxazol-5-yl)ethanol is then oxidized to theketone, i.e., 1-(3-(4-fluorophenyl)-isoxazol-5-yl)ethanone, which maythen be converted to a compound of formula (I-A) by the methodsdescribed herein.

In a further embodiment, 1-(3-(4-fluorophenyl)-isoxazol-5-yl)ethanol and1-(3-(4-fluorophenyl)-isoxazol-5-yl)ethanone are prepared according tothe methodology and reagents of Scheme 12B. 4-Fluoro-benzaldehyde isreacted with hydroxylamine hydrochloride to provide 4-fluorobenzaldehydeoxime. In one embodiment, the reaction is performed in methanol andsodium carbonate. In another embodiment, the reaction is performed atabout room temperature for about 4 hours. The isoxazole ring is thengenerated by reacting this intermediate with 3-hydroxy-butyne and NCS(about 1.2 equivalents) to provide1-(3-(4-fluorophenyl)isoxazol-5-yl)ethanol. In one embodiment, thiscyclization is performed in dichloromethane at about 40° C.1-(3-(4-Fluorophenyl)isoxazol-5-yl)ethanol is then oxidized to1-(3-(4-fluorophenyl)-isoxazol-5-yl)ethanone using Dess-Martinperiodinane. In one embodiment, the reaction is performed indichloromethane. In another embodiment, the reaction is performed atroom temperature for about 16 hours.

Scheme 13 provides another preparation of an intermediate useful herein,i.e., compound [TT]. In this embodiment, an amide-substituted “A” analog[RR] is converted to a 1,3,4-oxathiazol-2-one derivative [SS] by itsreaction with chloro-carbonylsulfenyl chloride. Intermediate [SS] isthen converted to intermediate [TT] by reaction with norbornadiene usingmicrowave irradiation or at high temperature.

In an additional embodiment, the amide group of 4-fluorobenzamide isconverted to a 1,3,4-oxathiazol-2-one group using chlorocarbonylsulfenylchloride. In one embodiment, the reaction is performed in toluene atabout room temperature. The resultant compound, i.e.,3-(4-fluoro-phenyl)-1,3,4-oxathiazol-5-one is then converted to anisothiazole ring using microwave (MW) irradiation in the presence ofnorbornadiene to provide 3-(4-fluorophenyl)isothiazole. In oneembodiment, the microwave irradiation is applied at a temperature ofabout 170° C. for about thirty minutes. 3-(4-Fluorophenyl)isothiazolemay then be converted to a compound of Formula (I) as described herein.

In another embodiment, intermediate [YY] may be prepared by acyclization reaction as provided in Scheme 14. In this embodiment,compound [UU] is reacted with 1,2-diethoxy-1,2-ethanedione. Theresultant intermediate [VV] is reacted with hydrazine hydrate to providethe A-substituted pyrazole ring intermediate [WW]. The ethyl acetatesubstituent of the pyrazole ring of compound [WW] is then reduced toprovide compound [XX]. In one embodiment, the reduction is performedusing lithium aluminum hydride, lithium borohydride or diisobutylaluminum hydride. The resultant hydroxymethylene substituent of thepyrazole ring is then oxidized to a carbaldehyde substituent to providecompound [YY]. In one embodiment, the oxidation is performed using PCCand provides carbaldehyde [YY]. Compound [YY] may then be converted to acompound of Formula (I-A) using the methods described herein.

In a further embodiment, a pyrazole cyclization reaction is provided inScheme 14A. In this embodiment, 1-(4-fluorophenyl)ethanone is reactedwith diethyl oxalate to provide ethyl4-(4-fluorophenyl)-2,4-dioxobutanoate. In one embodiment, this reactionis performed in the presence of a base such as potassium tert-butoxide.In another embodiment, this reaction is performed at about roomtemperature for about 24 hours. The pyrazole ring is then generated byreaction of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate with hydrazinehydrate to provide ethyl 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate.In one embodiment, this reaction is performed in at elevatedtemperatures. In another embodiment, this reaction is performed inethanol and glacial acetic acid for about 2 to 16 hours. Ethyl3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate is then reduced withlithium aluminum hydride to provide3-(4-fluorophenyl)-1H-pyrazol-5-yl-methanol. In one embodiment, thereduction is performed in THF at a temperature of about 0° C. to aboutroom temperature overnight.3-(4-Fluorophenyl)-1H-pyrazole-5-carbaldehyde is then formed byoxidizing 3-(4-fluorophenyl)-1H-pyrazole-5-methanol. In one embodiment,the oxidation is performed using PCC. In another embodiment, theoxidation is performed in dichloromethane at about room temperatureovernight. 3-(4-Fluorophenyl)-1H-pyrazole-5-carbaldehyde may thenconverted to a compound of Formula (I-A) using the methods describedherein.

Scheme 15 describes the preparation of compounds similar to thoseprepared in Scheme 14, but drawn to isoxazole rings. In this embodiment,compound [UU] is reacted with diethyl oxalate. The resultantintermediate [VV] is reacted with hydroxylamine hydrochloride to providethe A-substituted isoxazole ring intermediate [ZZ]. The ethyl acetatesubstituent of the isoxazole ring of [ZZ] is then reduced. In oneembodiment, the reduction is performed using a reducing agent such aslithium aluminum hydride, lithium borohydride or diisobutyl aluminumhydride. The resultant hydroxymethylene substituent of the oxazole ringof [AAA] is then oxidized to a carbaldehyde substituent, i.e., compound[BBB]. In one embodiment, the oxidation is performed using an oxidizingagent such as PCC or MnO₂. Compound [BBB] is then converted to acompound of Formula (I-A) by the methods described herein.

In a further embodiment, an isoxazole cyclization reaction is providedin Scheme 15A. In this embodiment, 1-(4-fluorophenyl)ethanone is reactedwith diethyl oxalate to provide ethyl4-(4-fluorophenyl)-2,4-dioxobutanoate. In one embodiment, this reactionis performed in the presence of a base such as potassium tert-butoxide.In another embodiment, this reaction is performed at about roomtemperature for about 24 hours. The isoxazole ring is then generated byreaction of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate withhydroxylamine hydrochloride to provide ethyl5-(4-fluorophenyl)isoxazole-3-carboxylate. In one embodiment, thisreaction is performed in at elevated temperatures. In anotherembodiment, this reaction is performed in ethanol for about 2 hours.Ethyl 5-(4-fluorophenyl)-isoxazole-3-carboxylate is then reduced withlithium aluminum hydride to provide5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, thereduction is performed in THF, at a temperature of about 0° C. to aboutroom temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehydeis then formed by oxidizing (5-(4-fluorophenyl)isoxazol-3-yl)methanol.In one embodiment, the oxidation is performed using PCC. In anotherembodiment, the oxidation is performed in dichloromethane at about roomtemperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde maythen converted to a compound of Formula (I-A) using the methodsdescribed herein.

In yet another embodiment, intermediate [CCC] may be prepared accordingto the methodology and reagents described in Scheme 16. In thisembodiment, an A-substituted amide [RR] is reacted withchlorocarbonylsulfenyl chloride to provide the A-substituted1,3,4-oxathiazol-2-one ring [SS]. The 1,3,4-oxathiazol-2-one fragment isthen converted to the corresponding 1,2,4-thiadiazole fragment viareaction with acetyl cyanide to provide the A-substituted1-(1,2,4-thiadiazol-5-yl)ethanone intermediate [CCC]. Compound [CCC] maythen be converted to a compound of Formula (I-A) by the methodsdescribed herein, such as Scheme 1.

In still a further embodiment,1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone may be preparedaccording to the methodology and reagents of Scheme 16A. In thisembodiment, a 1,3,4-oxathiazol-2-one ring fragment is generated andsubsequently converted to a 1,2,4-thiadiazole ring fragment during thepreparation of 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone.Specifically, 4-fluoro-benzamide is reacted with chlorocarbonylsulfenylchloride to provide 5-(4-fluoro-phenyl)-1,3,4-oxathiazol-2-one. In oneembodiment, the reaction is performed in toluene. In another embodiment,the reaction is performed at elevated temperatures of about 80° C. forabout 3 hours. 5-(4-Fluorophenyl)-1,3,4-oxathiazol-2-one is then reactedwith acetyl cyanide to provide1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)-ethanone. In oneembodiment, this reaction is performed in 1,2-dichlorobenzene. Inanother embodiment, this reaction is performed at elevated temperaturesof about 160° C. for about 20 hours.1-(3-(4-Fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone is then convertedto a compound of Formula (I-A) by the methods described herein, such asScheme 1.

In a further embodiment, intermediate [EEE] may be prepared according tothe methodology and reagents of Scheme 17. In this embodiment, themethods as described for Scheme 4 or Scheme 7, for example, may be usedto prepare intermediate [DDD]. Intermediate [DDD] is then reacted with atin reagent to convert the bromide in compound [DDD] to an acetyl groupin intermediate [EEE]. In one embodiment, the tin reagent istributyl(1-ethoxyvinyl)stannane. Compound [EEE] may then be converted toa compound of Formula (I-A) by the methods described herein, such asScheme 1.

In another embodiment,1-(5-(4-fluorophenyl)-1,2,4-thiadiazol-3-yl)ethanone is preparedaccording to the methodology and reagents of Scheme 17A. Specifically,4-fluorophenyl boronic acid is reacted with3-bromo-5-chloro-1,2,4-thiadiazole to provide3-bromo-5-(4-fluorophenyl)-1,2,4-thiadiazole.3-Bromo-5-(4-fluorophenyl)-1,2,4-thiadiazole is then reacted with a tinreagent such as tributyl(1-ethoxyvinyl)-stannane to convert the bromidemoiety of 3-bromo-5-(4-fluorophenyl)-1,2,4-thiadiazole to an acetylgroup. In one embodiment, this reaction is performed in the presence ofa catalyst such as PdCl₂(PPh₃)₄. In another embodiment, the reaction isperformed in DMF at elevated temperatures overnight.1-(5-(4-Fluorophenyl)-1,2,4-thiadiazol-3-yl)-ethanone may then convertedto a compound of Formula (I-A) by the methods described herein, such asScheme 1.

Compounds of Formula (I-B) may be prepared from compounds of Formula (I)where Q=O, by the method described in Scheme 18. In this method, acompound of Formula (I) where Q=O is first treated under acidicconditions to form the acetyl amide derivative [I-C]. In one embodiment,the reaction is carried out in acetonitrile. In another embodiment, thereaction is performed at elevated temperatures such as at 90° C. In afurther embodiment, the reaction is performed, in the presence of astrong acid such as concentrated sulfuric acid. The amide intermediate[I-C] is then hydrolyzed to provide compounds of Formula (I-B). In oneembodiment, the hydrolysis reaction is performed using a strong acidsuch as hydrochloric acid. In another embodiment, the hydrolysis isperformed at elevated temperatures. In a further embodiment, thehydrolysis is performed by heating intermediate [I-C] in aqueoushydrochloric acid in a sealed tube at about 100° C. for several hours,such as 24 hours, to provide compounds of Formula (I-B).

Acetyl and other ester prodrugs of compounds of Formula (I) where Q=O,i.e., compound (I-D), may be prepared using the methods describedherein. In one embodiment, a compound of Formula (I) where Q=O may bereacted with a acyl chloride. In another embodiment, the acyl chloridemay be R^(Z)C(O)Cl. In a further embodiment, the reaction may beperformed in the presence of a base such as potassium tert-butoxide, toprovide prodrug compound [I-D] as described in Scheme 19A.

Acetyl and other amide prodrugs of compounds of Formula (I) where Q=NH,i.e., compound (I-E), may be prepared by using the methods describedherein. In one embodiment, compounds of Formula (I-B) are reacted withan acyl chloride. In another embodiment, the acyl chloride isR^(Z)C(O)Cl. In a further embodiment, the reaction may be performed inthe presence of a base such as pyridine.

As well, acetyl amide prodrugs of compounds of Formula (I-E) may beprepared by reaction of a compound of Formula (I-A) where Q=O withacetonitrile. In one embodiment, the reaction is performed under acidicconditions to provide prodrug compound [I-E] as described in Scheme 19C.

Pharmaceutical compositions useful herein contain a compound of formula(I) in a pharmaceutically acceptable carrier optionally with otherpharmaceutically inert or inactive ingredients. In another embodiment, acompound of formula (I) is present in a single composition. In a furtherembodiment, a compound of formula (I) is combined with one or moreexcipients and/or other therapeutic agents as described below.

The pharmaceutical compositions of the invention comprise an amount of acompound of formula (I) or a pharmaceutically acceptable salt or prodrugthereof that is effective for regulating CYP17 activity in a subject.Specifically, the dosage of the compound of formula (I) to achieve atherapeutic effect will depend on the formulation, age, weight and sexof the patient and route of delivery. It is also contemplated that thetreatment and dosage of the compound of formula (I) may be administeredin unit dosage form and that one skilled in the art would adjust theunit dosage form accordingly to reflect the relative level of activity.The decision as to the particular dosage to be employed (and the numberof times to be administered per day) is within the discretion of theordinarily-skilled physician, and may be varied by titration of thedosage to the particular circumstances to produce the desiredtherapeutic effect. In one embodiment, the therapeutically effectiveamount is about 0.01 mg/kg to 10 mg/kg body weight. In anotherembodiment, the therapeutically effective amount is less than about 5g/kg, about 500 mg/kg, about 400 mg/kg, about 300 mg/kg, about 200mg/kg, about 100 mg/kg, about 50 mg/kg, about 25 mg/kg, about 10 mg/kg,about 1 mg/kg, about 0.5 mg/kg, about 0.25 mg/kg, about 0.1 mg/kg, about100 μg/kg, about 75 μg/kg, about 50 μg/kg, about 25 μg/kg, about 10μg/kg, or about 1 μg/kg. However, the therapeutically effective amountof the compound of formula (I) can be determined by the attendingphysician and depends on the condition treated, the compoundadministered, the route of delivery, the age, weight, severity of thepatient's symptoms and response pattern of the patient.

The therapeutically effective amounts may be provided on regularschedule, i.e., daily, weekly, monthly, or yearly basis or on anirregular schedule with varying administration days, weeks, months, etc.Alternatively, the therapeutically effective amount to be administeredmay vary. In one embodiment, the therapeutically effective amount forthe first dose is higher than the therapeutically effective amount forone or more of the subsequent doses. In another embodiment, thetherapeutically effective amount for the first dose is lower than thetherapeutically effective amount for one or more of the subsequentdoses. Equivalent dosages may be administered over various time periodsincluding, but not limited to, about every 2 hours, about every 6 hours,about every 8 hours, about every 12 hours, about every 24 hours, aboutevery 36 hours, about every 48 hours, about every 72 hours, about everyweek, about every two weeks, about every three weeks, about every month,and about every two months. The number and frequency of dosagescorresponding to a completed course of therapy will be determinedaccording to the judgment of a health-care practitioner. Thetherapeutically effective amounts described herein refer to totalamounts administered for a given time period; that is, if more than onecompound of formula (I) or a pharmaceutically acceptable salt or prodrugthereof is administered, the therapeutically effective amountscorrespond to the total amount administered.

The pharmaceutical compositions containing a compound of formula (I) maybe formulated neat or with one or more pharmaceutical carriers foradministration. The amount of the pharmaceutical carrier(s) isdetermined by the solubility and chemical nature of the compound offormula (I), chosen route of administration and standard pharmacologicalpractice. The pharmaceutical carrier(s) may be solid or liquid and mayincorporate both solid and liquid carriers. A variety of suitable liquidcarriers is known and may be readily selected by one of skill in theart. Such carriers may include, e.g., DMSO, saline, buffered saline,hydroxypropylcyclodextrin, and mixtures thereof. Similarly, a variety ofsolid carriers and excipients are known to those of skill in the art.The compounds of formula (I) may be administered by any route, takinginto consideration the specific condition for which it has beenselected. The compounds of formula (I) may, be delivered orally, byinjection, inhalation (including orally, intranasally andintratracheally), ocularly, transdermally, intravascularly,subcutaneously, intramuscularly, sublingually, intracranially,epidurally, intravesically, rectally, and vaginally, among others.

Although the compound of formula (I) may be administered alone, it mayalso be administered in the presence of one or more pharmaceuticalcarriers that are physiologically compatible. The carriers may be in dryor liquid form and must be pharmaceutically acceptable. Liquidpharmaceutical compositions are typically sterile solutions orsuspensions. When liquid carriers are utilized for parenteraladministration, they are desirably sterile liquids. Liquid carriers aretypically utilized in preparing solutions, suspensions, emulsions,syrups and elixirs. In one embodiment, the compound of formula (I) isdissolved a liquid carrier. In another embodiment, the compound offormula (I) is suspended in a liquid carrier. One of skill in the art offormulations would be able to select a suitable liquid carrier,depending on the route of administration. The compound of formula (I)may alternatively be formulated in a solid carrier. In one embodiment,the composition may be compacted into a unit dose form, e.g., tablet orcaplet. In another embodiment, the composition may be added to unit doseform, e.g., a capsule. In a further embodiment, the composition may beformulated for administration as a powder. The solid carrier may performa variety of functions, e.g., may perform the functions of two or moreof the excipients described below. For example, solid carrier may alsoact as a flavoring agent, lubricant, solubilizer, suspending agent,filler, glidant, compression aid, binder, disintegrant, or encapsulatingmaterial.

The composition may also be sub-divided to contain appropriatequantities of the compound of formula (I). For example, the unit dosagecan be packaged compositions, e.g., packeted powders, vials, ampoules,prefilled syringes or sachets containing liquids.

Examples of excipients which may be combined with one or more compoundof formula (I) include, without limitation, adjuvants, antioxidants,binders, buffers, coatings, coloring agents, compression aids, diluents,disintegrants, emulsifiers, emollients, encapsulating materials,fillers, flavoring agents, glidants, granulating agents, lubricants,metal chelators, osmo-regulators, pH adjustors, preservatives,solubilizers, sorbents, stabilizers, sweeteners, surfactants, suspendingagents, syrups, thickening agents, or viscosity regulators. See, forexample, the excipients described in the “Handbook of PharmaceuticalExcipients”, 5^(th) Edition, Eds.: Rowe, Sheskey, and Owen, APhAPublications (Washington, D.C.), Dec. 14, 2005, which is incorporatedherein by reference.

In one embodiment, the compositions may be utilized as inhalants. Forthis route of administration, compositions may be prepared as fluid unitdoses using a compound of formula (I) and a vehicle for delivery by anatomizing spray pump or by dry powder for insufflation.

In another embodiment, the compositions may be utilized as aerosols,i.e., oral or intranasal. For this route of administration, thecompositions are formulated for use in a pressurized aerosol containertogether with a gaseous or liquefied propellant, e.g.,dichlorodifluoromethane, carbon dioxide, nitrogen, propane, and thelike. Also provided is the delivery of a metered dose in one or moreactuations.

In another embodiment, the compositions may be administered by asustained delivery device. “Sustained delivery” as used herein refers todelivery of a compound of formula (I) which is delayed or otherwisecontrolled. Those of skill in the art know suitable sustained deliverydevices. For use in such sustained delivery devices, the compound offormula (I) is formulated as described herein.

In addition to the components described above for use in the compositionand the compound of formula (I), the compositions may contain one ormore medications or therapeutic agents which are used to treat solidtumors. In one embodiment, the medication is a chemotherapeutic,including but not limited to cytotoxic/cytostatic agents and targetedagents such as include LHRH agonist/antagonists, androgen receptorantagonists, kinase or other enzyme inhibitors, and the like. Examplesof chemotherapeutics include those recited in the “Physician's DeskReference”, 64^(th) Edition, Thomson Reuters, 2010, which is herebyincorporated by reference. In one embodiment, the compounds of formula(I) can be administered with other inhibitors of CYP17, such asabiraterone acetate, or with compounds that suppress testosteroneproduction, such as LHRH agonists/antagonists. Therapeutically effectiveamounts of the additional medication(s) or therapeutic agents are wellknown to those skilled in the art. However, it is well within theattending physician to determine the amount of other medication to bedelivered.

The compounds of formula (I) and/or other medication(s) or therapeuticagent(s) may be administered in a single composition. However, thepresent invention is not so limited. In other embodiments, the compoundsof formula (I) may be administered in one or more separate formulationsfrom other compounds of formula (I), chemotherapeutic agents, or otheragents as is desired.

Also provided herein are kits or packages of pharmaceutical formulationscontaining the compounds of formula (I) or compositions describedherein. The kits may be organized to indicate a single formulation orcombination of formulations to be taken at each desired time.

Suitably, the kit contains packaging or a container with the compound offormula (I) formulated for the desired delivery route. Suitably, the kitcontains instructions on dosing and an insert regarding the activeagent. Optionally, the kit may further contain instructions formonitoring circulating levels of product and materials for performingsuch assays including, e.g., reagents, well plates, containers, markersor labels, and the like. Such kits are readily packaged in a mannersuitable for treatment of a desired indication. For example, the kit mayalso contain instructions for use of a spray pump or other deliverydevice. Other suitable components to include in such kits will bereadily apparent to one of skill in the art, taking into considerationthe desired indication and the delivery route.

The compounds of formula (I) or compositions described herein can be asingle dose or for continuous or periodic discontinuous administration.For continuous administration, a package or kit can include the compoundof formula (I) in each dosage unit (e.g., solution, lotion, tablet,pill, or other unit described above or utilized in drug delivery), andoptionally instructions for administering the doses daily, weekly, ormonthly, for a predetermined length of time or as prescribed. When thecompound of formula (I) is to be delivered periodically in adiscontinuous fashion, a package or kit can include placebos duringperiods when the compound of formula (I) is not delivered. When varyingconcentrations of a composition, of the components of the composition,or the relative ratios of the compounds of formula (I) or agents withina composition over time is desired, a package or kit may contain asequence of dosage units which provide the desired variability.

A number of packages or kits are known in the art for dispensingpharmaceutical agents for periodic oral use. In one embodiment, thepackage has indicators for each period. In another embodiment, thepackage is a labeled blister package, dial dispenser package, or bottle.

The packaging means of a kit may itself be geared for administration,such as an inhaler, syringe, pipette, eye dropper, or other suchapparatus, from which the formulation may be applied to an affected areaof the body, such as the lungs, injected into a subject, or even appliedto and mixed with the other components of the kit.

The compositions of these kits also may be provided in dried orlyophilized forms. When reagents or components are provided as a driedform, reconstitution generally is by the addition of a suitable solvent.It is envisioned that the solvent also may be provided in anotherpackage.

The kits of the present invention also will typically include a meansfor containing the vials in close confinement for commercial sale suchas, e.g., injection or blow-molded plastic containers into which thedesired vials are retained. Irrespective of the number or type ofpackages and as discussed above, the kits also may include, or bepackaged with a separate instrument for assisting with theinjection/administration or placement of the composition within the bodyof an animal. Such an instrument may be an inhaler, syringe, pipette,forceps, measuring spoon, eye dropper or any such medically approveddelivery means.

In one embodiment, a kit is provided and contains a compound of formula(I). The compound of formula (I) may be in the presence or absence ofone or more of the carriers or excipients described above. The kit mayoptionally contain instructions for administering the medication and thecompound of formula (I) to a subject having a disease associated withCPY17 activity.

In a further embodiment, a kit is provided and contains a compound offormula (I) in a second dosage unit, and one or more of the carriers orexcipients described above in a third dosage unit. The kit mayoptionally contain instructions for administering the medication and thecompound of formula (I) to a subject having a disease associated withCPY17 activity.

The compounds described herein are useful in treating conditions whichare associated with CPY17 activity. In one embodiment, such a disease isassociated with abnormal cellular proliferation, particularly theabnormal proliferation of cells which is sensitive to hormones such astestosterone or estrogen. The term “abnormal cellular proliferation”refers to the uncontrolled growth of cells which are naturally presentin a mammalian body. In one embodiment, a disease which is characterizedby abnormal cellular proliferation is cancer, including, withoutlimitation, cancer of the prostate, head, neck, eye, mouth, throat,esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum,stomach, bladder, uterus, cervix, breast, ovaries, vagina, testicles,skin, thyroid, blood, lymph nodes, kidney, liver, intestines, pancreas,brain, central nervous system, adrenal gland, or skin or a leukemia. Inone embodiment, the disease characterized by abnormal cellularproliferation is cancer of the prostate.

The term “regulation” or variations thereof as used herein refers to theability of a compound of formula (I) to inhibit one or more componentsof a biological pathway. In one embodiment, “regulation” refers toinhibition of CPY17 activity.

In one embodiment, methods for inhibiting CPY17 activity are providedwhich comprise administering a therapeutically effective amount of acompound of formula (I) to a patient in need thereof.

In another embodiment, methods for treating a disease characterized byan abnormal cellular growth associated with CPY17 activity are providedwhich comprise administering of a therapeutically effective amount of acompound of formula (I) to a patient in need thereof.

In a further embodiment, methods for treating a condition treatable byinhibiting CPY17 activity are provided which comprise administering atherapeutically effective amount of a compound of formula (I) to apatient in need thereof.

In still another embodiment, methods for treating cancer are providedwhich comprise administering a therapeutically effective amount of acompound of formula (I) to a patient in need thereof.

In yet a further embodiment, methods for treating prostate cancer areprovided which comprise administering a therapeutically effective amountof a compound of formula (I) to a patient in need thereof.

In a still further embodiment, methods of reducing testosteroneproduction in a patient are provided which comprise administering atherapeutically effective amount of a compound of formula (I) in needthereof.

As described herein, a therapeutically effective amount of a compoundwhen used for the treatment of cancer is an amount which may reduce thenumber of cancer cells (cytoxic), allow the number of cancer cells toremain relatively constant (cytostatic), reduce tumor size, inhibitmetastasis, inhibit tumor growth and/or ameliorate one or more of thesymptoms of the cancer. For cancer therapy, efficacy can be measured forexample, by assessing the time to disease progression, measuring tumorsize and/or determining the patient response rate.

The following examples are illustrative only and are not intended tolimit the present invention.

EXAMPLES

All reactions were carried out under dry nitrogen or argon atmosphereunless otherwise specified. Unless otherwise stated, all the rawstarting materials, solvents and reagents were purchased from commercialsources (e.g., Avocado Research Chemicals, Apollo Scientific Limited,Bepharma Ltd., Combi-Blocks Inc., Sigma Aldrich Chemicals Pvt. Ltd.,Ultra Labs, Toronto Research Chemicals Inc., Chemical House, RFCLLimited, Spectro Chem Pvt. Ltd., Leonid Chemicals, Loba Chemie,Changzhou Yangyuan, NeoSynth., Rankem) and used as such without furtherpurification, or reagents can be synthesized by procedures known in theart.

The following abbreviations are used and have the indicated definitions:MHz is megahertz (frequency), m is multiplet, t is triplet, d isdoublet, s is singlet, br is broad, CDCl₃ is deutero chloroform, calcdis calculated, min is minutes, h is hours, g is grams, mmol ismillimoles, mL is milliliters, N is Normal (concentration), M ismolarity (concentration), μM is micromolar, ee is enantiomeric excess, °C. is degree centigrade, HPLC is High Performance Liquid Chromatography,LC-MS is Liquid Chromatography-Mass Spectroscopy, NMR is NuclearMagnetic Resonance, TLC is thin layer chromatography, THF istetrahydrofuran, MeOH is methanol, DCM is dichloromethane, DEA isdiethylamine, DMA is dimethylacetamide, DMF is N,N-dimethyl formamide,DMSO is dimethyl sulfoxide, EtOH is ethyl alcohol, EtOAc is ethylacetate, MeOH is methanol, RT is room temperature, HCl is hydrogenchloride or hydrochloric acid, TFA is trifluoroacetic acid, EtMgBr isethyl magnesium bromide, n-BuLi is n-butyl lithium, NaHCO₃ is sodiumbicarbonate, Na₂CO₃ is sodium carbonate, Na₂SO₄ is sodium sulfate, DCCis N,N-dicyclohexylcarbodiimide, DIPA is diisopropylamine, LDA islithium diisopropylamine, HOBt is N-hydroxy-benzotriazole, NCS isN-chlorosuccinimide, and TBAB is tetrabutyl ammonium bromide.

Biotage Isolera® One and CombiFlash® (Teledyne Isco) Automated FlashPurification System were used for the purification of crude productsusing the eluent combination mentioned in the respective procedures.Flash Chromatography was performed using silica gel (60-100, 100-200 and230-400 mesh) from ChemLabs, with nitrogen and/or compressed air.Preparative thin-layer chromatography was carried out using silica gel(GF 1500 μM 20×20 cm and GF 2000 μM 20×20 cm Prep-scored plates fromAnaltech, Inc. Delaware, USA). Thin-layer chromatography was carried outusing pre-coated silica gel sheets (Merck 60 F₂₅₄). Visual detection wasperformed with ultraviolet light, p-anisaldehyde stain, ninhydrin stain,dinitrophenyl hydrazine stain, potassium permanganate stain, or iodine.Reactions at lower temperature were performed by using cold baths, e.g.,H₂O/ice at 0° C., and acetone/dry ice at −78° C. Melting points weredetermined by using a LabIndia visual melting range apparatus. ¹H NMRspectra were recorded at 400 MHz with a Varian V400 spectrometer, Bruker400 (unless otherwise noted) at ambient temperature, usingtetramethylsilane as internal reference. The chemical shift values arequoted in δ (parts per million). Mass spectra of all the intermediatesand final compounds were recorded using Acquity® UPLC-SQD (Waters) &Agilent 1290 Infinity® with 6150 SQD machines. HPLC spectra wererecorded using Agilent 1290 Infinity® UHPLC and Alliance (Waters)systems. LCMS spectra were recorded using Agilent 1200® LCMS/Agilent1290® UHPLC-SQD with diode array detector (DAD) detection LC-MSinstruments using a BEH C18 column and Zorbax® HD C18 column (50 mm×2.1mm×1.7μ) & (50 mm×2.1 mm×1.8μ), a mobile phase of 0.01% of acetic acidwith acetonitrile and 0.01% of acetic acid with methanol, a flow rate of0.3 mL/min, a temperature of 70 and 50° C., and a run time of 3.0 and/or5 min. The purity of each of the final compounds was detected usingWaters® PDA with SQD and Aglient® DAD with 6150 SQD instruments and thefollowing conditions:

Condition 1: Column: BEH C18 (Waters); mobile phase: 0.01% acetic acidwith acetonitrile & 0.01% acetic acid with methanol; gradient: (B/% T):0/0, 1.2/100, 2.5/100, 2.8/0, 3.0/0; flow: 0.3 mL/min; temperature: 70°C.; run time: 3.0 min.

Condition 2: Column: Zorbax® HD C18; mobile phase: 0.01% acetic acidwith acetonitrile & 0.01% acetic acid with methanol; gradient: (B/% T):0/0, 2.5/100, 4.5/100, 4.8/0, 5.0/0; flow: 0.3 mL/min; temperature: 50°C.; run time: 5.0 min

Example 1 1-(5-(4-Methoxyphenyl)pyridin-2-yl)-1-(pyridin-4-yl)ethanol(synthetic method of Scheme 1)

Step 1: 1-(5-(4-Methoxyphenyl)pyridin-2-yl)ethanone

To a stirred solution of toluene and ethanol (9 mL, 2:1) of1-(5-bromopyridin-2-yl)ethanone (200 mg, 1 mmol) was added(4-methoxyphenyl) boronic acid (304 mg, 2 mmol), 2M Na₂CO₃ (2.84 mL),and Pd(PPh₃)₄ (11 mg, 0.01 mmol) under argon atmosphere and heating wascontinued for 5 hours at 70° C. The reaction mixture was concentratedunder vacuum and diluted with water (100 mL) and extracted with EtOAc(2×200 mL). The combined extracts were washed with brine solution (20mL), and organic layer was dried over Na₂SO₄ and concentrated undervacuum to obtain crude product. This, on purification by flashchromatography (silica gel, 60-120μ) using 10% ethyl acetate in hexaneeluent, afforded 1-(5-(4-methoxyphenyl)pyridin-2-yl)ethanone asoff-white solid (200 mg, 88% yield). 1H NMR (400 MHz, DMSO-d₆): δ 8.99(d, 1H), 8.20 (dd, 1H), 7.97 (d, 1H), 7.76 (d, 2H), 7.07 (d, 2H), 3.81(s, 3H), 2.63 (s, 3H); LC-MS m/z calculated for [M+H]⁺ 228.27, found228.4.

Step 2: 1-(5-(4-Methoxyphenyl)pyridin-2-yl)-1-(pyridin-4-yl)ethanol

To cooled (−78° C.) 4-iodopyridine (270 mg, 1.3 mmol) [Albrecht, et al.,US Patent Application Publication No. 2009/0318436] in THF (15 mL) wasadded slowly 1.6 M n-BuLi in hexane (1.65 mL, 2.6 mmol). Stirring wascontinued for an additional 30 minutes at the same temperature, followedby the addition of a THF (5 mL) solution of1-(5-(4-methoxyphenyl)pyridin-2-yl)ethanone (300 mg, 1.3 mmol). Afterstirring for 2 hours at the same temperature, the reaction mixture wasquenched with saturated aqueous NH₄Cl solution (10 mL). The aqueouslayer was extracted with ethylacetate (2×150 mL). The combined organiclayers were washed with brine (20 mL). Finally, the organic phase wasdried over Na₂SO₄ and concentrated under reduced pressure to give crudeproduct. The crude product was purified by flash chromatography (silicagel 60-120μ) using 20% ethyl acetate and hexane as eluent to affordracemic 1-(5-(4-methoxyphenyl)pyridin-2-yl)-1-(pyridin-4-yl)ethanol asan off-white solid (135 mg, 33% yield) in 99.6% HPLC purity. 1H NMR (400MHz, DMSO-d₆): δ 8.74 (d, 1H), 8.45 (dd, 2H), 7.98 (dd, 1H), 7.68 (d,1H), 7.62 (d, 2H), 7.48 (dd, 2H), 7.02 (d, 2H), 6.15 (s, 1H), 3.78 (s,3H), 1.88 (s, 3H); LC-MS m/z calculated for [M+H]⁺307.14, found 307.3.

Examples 2 & 3 Enantiomer #1 and Enantiomer #2 of1-(5-(4-methoxyphenyl)-pyridin-2-yl)-1-(pyridin-4-yl)ethanol

Racemic 1-(5-(4-methoxyphenyl)pyridin-2-yl)-1-(pyridin-4-yl)ethanol (100mg) was subjected to chiral HPLC purification using a Chiralpak® IC [250mm×4.6 mm×5μ column, mobile phase: n-heptane:ethanol with 0.01% DEA(50:50); flow rate: 1 mL/min] to afford 33 mg (66% recovery) of1-(5-(4-methoxyphenyl)pyridin-2-yl)-1-(pyridin-4-yl)ethanol (Enantiomer#1) and 33 mg (66% recovery) of1-(5-(4-methoxyphenyl)pyridin-2-yl)-1-(pyridin-4-yl)ethanol (Enantiomer#2), each with >99.5% ee. For each enantiomer: 1H NMR (400 MHz,DMSO-d₆): δ 8.74 (d, 1H), 8.45 (d, 2H), 7.98 (dd, 1H), 7.69 (d, 1H),7.62 (d, 2H), 7.48 (d, 2H), 7.02 (d, 2H), 6.15 (s, 1H), 3.78 (s, 3H),1.87 (s, 3H); LC-MS m/z calculated for [M+H]⁺ 307.14, found 307.1

Example 7 1-(2-(4-Fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol

A. Preparation A According to the Synthetic Method of Schemes 1 and 2Step 1: 2-(4-Fluorophenyl)thiazole-5-carbaldehyde

To a solution of 2-bromothiazole-5-carbaldehyde (5.0 g, 26.04 mmol) intoluene (150 mL) and ethanol (75 mL) was added (4-fluorophenyl)boronicacid (7.29 g, 52.08 mmol), 2M sodium carbonate solution (73.58 mL),Pd(PPh₃)₄ (1.5 g, 1.3 mmol) under argon atmosphere. The resultingmixture was heated at 85° C. for 6 h. The reaction mixture wasconcentrated under reduced pressure, the residue was diluted with water(150 mL), and extracted with ethyl acetate (5×500 mL). The organic layerwas dried over Na₂SO₄, filtered and concentrated under reduced pressuresto obtain crude product. The crude product was purified by Combiflash®chromatography (Mobile phase: 10% ethyl acetate in hexane) to give2-(4-fluorophenyl)thiazole-5-carbaldehyde as off-white solid (200 mg,88% yield). 1H NMR (400 MHz, DMSO-d₆): δ 10.06 (s, 1H), 8.74 (s, 1H),8.14-8.11 (m, 2H), 7.39 (t, 2H); LC-MS m/z calculated for [M+H]⁺ 208.02,found 207.9.

Step 2: 1-(2-(4-Fluorophenyl)thiazol-5-yl)ethanol

To a solution of 2-(4-fluorophenyl)thiazole-5-carbaldehyde (500 mg, 2.41mmol) in THF (25 mL) was added 3M methyl magnesium bromide in ether(1.61 mL, 4.83 mmol) slowly at 0° C. The reaction mixture stirred for 1hour at 0° C. and then at room temperature for about 1 hour. Thereaction mixture was quenched with saturated NH₄Cl solution (25 mL),extracted with ethyl acetate (3×150 mL), the organic layer was driedover Na₂SO₄ and concentrated under reduced pressure to obtain crudeproduct. The crude product was purified by flash chromatography(100-200μ; 30% ethyl acetate in hexane) to afford1-(2-(4-fluorophenyl)thiazol-5-yl)ethanol as light yellow solid (420 mg,78% yield). 1H NMR (400 MHz, DMSO-d₆): δ 7.93 (t, 2H), 7.67 (s, 1H),7.30 (t, 2H), 5.71 (d, 1H), 5.01 (t, 1H), 1.45 (d, 3H); LC-MS m/zcalculated for [M+H]⁺ 224.05, found 224.4

Step 3: 1-(2-(4-Fluorophenyl)thiazol-5-yl)ethanone

A solution of 1-(2-(4-fluorophenyl)thiazol-5-yl)ethanol (1.0 g, 4.4mmol) in dichloromethane (40 mL) was cooled to 0° C. Dess-Martinperiodinane (5.7 g, 13.4 mmol) was added slowly at 0° C. and thereaction mixture stirred at room temperature for 2 h. The reactionmixture was quenched with saturated NaHCO₃ solution (80 mL), sodiumthiosulfate solution (20 mL), extracted with ether (2×1000 mL), theorganic layer dried over Na₂SO₄, filtered and concentrated to obtaincrude product. The crude product was purified by Combiflash®chromatography (40% ethyl acetate in hexane) to afford1-(2-(4-fluorophenyl)thiazol-5-yl)ethanone as off-white solid (820 mg,83% yield). 1H NMR (400 MHz, DMSO-d₆): δ 8.67 (s, 1H), 8.08 (t, 2H),7.37 (t, 2H), 2.59 (s, 3H); LC-MS m/z calculated for [M+H]⁺ 222.03,found 222.3.

Step 4: 1-(2-(4-Fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol

A solution 4-iodopyridine (1 g, 4.88 mmol) in THF (15 mL) was cooled to−78° C. under nitrogen, 1.6 M n-BuLi in hexane (0.565 mL, 8.14 mmol) wasslowly added at −78° C. The reaction mixture was stirred for 10 min and1-(2-(4-fluorophenyl)thiazol-5-yl)ethanone (900 mg, 4.07 mmol) in THF(25 mL) was added. The resulting mixture was stirred at −78° C. for 2 h.The reaction mixture was quenched with saturated NH₄Cl solution (160mL), extracted with ethyl acetate (3×250 mL), the organic layer driedover Na₂SO₄, filtered and concentrated under reduced pressure to obtaincrude product. The crude product was purified by flash chromatography(100-200μ; 70% ethyl acetate in hexane) to afford1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol as off-whitesolid (1.2 g, 35% yield) in 99.6% HPLC purity. 1H NMR (400 MHz,DMSO-d₆): δ 8.51 (d, 2H), 7.88-7.92 (m, 2H), 7.81 (s, 1H), 7.48 (d, 2H),7.28 (t, 2H), 6.64 (s, 1H), 1.93 (s, 3H); LC-MS m/z calculated for[M+H]⁺ 301.07, found 301.1.

B. Preparation B According to the Synthetic Method of Scheme 3 Step 1:2-(4-Fluorophenyl)thiazole

Using 2-bromothiazole (5.0 g, 30.482 mmol) and (4-fluorophenyl)boronicacid (8.528 g, 60.964 mmol) as reactants and following the proceduredescribed in Example 7 step 1, the title compound was obtained afterpurification by flash chromatography (60-120μ; 4% ethyl acetate inhexane) as colorless liquid (5.0 g, 91% yield). 1H NMR (400 MHz,DMSO-d₆): δ 8.00-7.89 (m, 2H), 7.90 (d, 1H), 7.76 (d, 1H), 7.32 (t, 2H);LC-MS m/z calculated for [M+H]⁺ 180.02, found 180.1.

Step 2: 1-(2-(4-Fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol

To a stirred solution of diisopropylamine (0.283 mL, 2.01 mmol) in THF(15 mL) at −78° C. under nitrogen atmosphere was added 1.6M n-BuLi inhexane (1.25 mL, 2.01 mmol) slowly. The reaction mixture was stirred for30 min at −5° C., cooled to −78° C., 2-(4-fluorophenyl)thiazole (300 mg,1.67 mmol) in THF (5 mL) added, and then 4-acetyl pyridine (300 mg, 1.67mmol) in THF (5 mL) added. The resulting mixture was stirred at −78° C.for 2 h. The reaction mixture was quenched with saturated NH₄Cl solution(40 mL) and extracted with ethyl acetate (4×150 mL). The organic layerwas dried over Na₂SO₄ and concentrated to obtain crude product. Thecrude product was purified by flash chromatography (100-200μ; 80% ethylacetate in hexane) to afford1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol as off-whitesolid (285 mg, 57% yield), HPLC purity 99.9%, mp 229-232° C. 1H NMR (400MHz, DMSO-d₆): δ 8.53 (d, 2H), 7.92 (t, 2H), 7.81 (s, 1H), 7.49 (d, 2H),7.30 (t, 2H), 6.66 (s, 1H), 1.93 (s, 3H); LC-MS m/z calculated for[M+H]⁺ 301.07, found 301.6.

HCl salt: To a suspension of1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol (2 g, 6.6mmol) in ethanol (120 ml) was added 1,4-dioxane HCl (4 M, 1.66 mL, 6.6mmol) slowly at 0° C., and then the mixture was stirred for 1 hour atroom temperature. The solid that formed was filtered and washed withhexane (10 mL) to afford4-(1-(1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanolhydrochloride as an off-white solid (1.6 g, 71% yield), HPLC purity99.7%, mp 229-232° C. 1H NMR (400 MHz, DMSO-d₆): 8.81 (d, 2H), 8.04 (d,2H), 7.92-7.89 (m, 3H), 7.29 (t, 2H), 7.13 (br s, 1H), 2.00 (s, 3H),LC-MS m/z calculated for [M+H]⁺ 301.07, found 301.1.

4-Methylbenzenesulfonic acid salt: To a suspension of1-(2-(4-fluorophenyl)-thiazol-5-yl)-1-(pyridin-4-yl)ethanol (2 g, 6.6mmol) in ethanol (60 mL) was added 4-methylbenzenesulfonic acid (1.14 g,6.6 mmol) slowly at 0° C., and then the mixture was stirred for 1 hourat room temperature. The solid that formed was filtered and washed withhexane (10 mL) to afford4-(1-(1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol4-methylbenzenesulfonic acid salt as an off-white solid (1.9 g, 61%yield), HPLC purity 98.2%, mp 181-184° C. 1H NMR (400 MHz, DMSO-d₆):8.84 (d, 2H), 8.08 (d, 2H), 7.91 (t, 3H), 7.46 (d, 2H), 7.30 (t, 2H),7.09 (d, 2H), 2.26 (s, 3H), 2.01 (s, 3H); LC-MS m/z calculated for[M+H]⁺ 301.07, found 301.1.

Benzenesulfonic acid salt: To a suspension of1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol (2 g, 6.6mmol) in ethanol (60 mL) was added benzenesulfonic acid (1.05 g, 6.6mmol) slowly at 0° C., and then the mixture was stirred for 1 hour atroom temperature. The reaction mixture was concentrated, the solidobtained was washed with hexane (10 mL) to afford4-(1-(1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanolbenzenesulfonic acid salt as off-white solid (1.3 g, 43% yield), HPLCpurity 99.6%, mp 165-167° C. 1H NMR (400 MHz, DMSO-d6): 8.81 (d, 2H),8.04 (d, 2H), 7.93-7.89 (m, 3H), 7.57 (d, 2H), 7.33-7.28 (m, 5H), 7.09(br s, 1H), 2.00 (s, 3H); LC-MS m/z calculated for [M+H]⁺ 301.07, found301.1.

Sulfuric acid salt: To a suspension of1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol (1 g, 3.3mmol) in ethanol (25 mL) was added H₂SO₄ (0.18 mL, 3.3 mmol) slowly at0° C., and then the mixture was stirred for 1 hour at room temperature.The solid that formed was filtered and washed with hexane (10 mL) toafford4-(1-(2-(4-fluorophenyl)thiazol-5-yl)-1-hydroxyethyl)pyridin-1-iumhydrogen sulfate as an off-white solid (500 mg, 38% yield), HPLC purity99.3%, mp 193-196° C. 1H NMR (400 MHz, DMSO-d₆): 8.82 (d, 2H), 8.05 (d,2H), 7.93-7.89 (m, 3H), 7.29 (t, 2H), 7.13 (br s, 1H), 2.00 (s, 3H);LC-MS m/z calculated for [M+H]⁺ 301.07, found 301.1.

Nitric acid salt: A suspension of1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol (2 g, 10mmol) in ethanol (6 mL) and isopropyl alcohol (30 mL) was cooled to 0°C., and to this mixture was added 6N HNO₃ (6 mL) in 30 mL of isopropylalcohol. The reaction mixture was stirred for 1 hour at roomtemperature. The solid formed was filtered and washed with hexane (10mL) to afford4-(1-(2-(4-fluorophenyl)thiazol-5-yl)-1-hydroxyethyl)pyridin-1-iumnitrate as an off-white solid (2.3 g, 63% yield), HPLC purity 99.8%, mp188-191° C. 1H NMR (400 MHz, DMSO-d₆): 8.85 (d, 2H), 8.10 (d, 2H), 7.92(t, 3H), 7.30 (t, 2H), 7.13 (br s, 1H), 2.01 (s, 3H); LC-MS m/zcalculated for [M+H]⁺ 301.07, found 301.1.

Examples 8 & 9 (Method 1) Enantiomer #1 and Enantiomer #2 of1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol

Racemic 1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol (500mg) (Example 7) was dissolved in 15 mL of 60:40 n-heptane/ethyl acetatemixture containing 500 μL TFA, and subjected to chiral HPLC purificationusing Chiralpak®IC [250 mm×4.6 mm×5 μm] column, mobile phase:n-heptane:ethanol with 0.1% DEA (60:40); flow rate: 1 mL/min]. Elutedfractions of the two enantiomers were separately collected andconcentrated to obtain a solid, which was dissolved in ethyl acetate andwashed with saturated aqueous sodium bicarbonate solution to afford(+)-1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol (Example8) (Enantiomer #1, [α]_(D) ^(26.5) +24.2 (c 1.0, DMF)) and(−)-1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol (Example9) (Enantiomer #2, [α]_(D) ^(26.6) −25.6 (c 1.0, DMF)). Each enantiomerwas isolated with >98.7% ee. For each enantiomer: 1H NMR (400 MHz,DMSO-d₆): δ 8.51 (d, 2H), 7.92-7.88 (t, 2H), 7.79 (s, 1H), 7.48 (d, 2H),7.28 (t, 2H), 6.64 (s, 1H), 1.92 (s, 3H); LC-MS m/z calculated for[M+H]⁺ 301.07, found 301.5.

Examples 8 & 9 (Method 2) Enantiomer #1 and Enantiomer #2 of1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol

Racemic 1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethyl acetate(150 mg) (Example 65) was dissolved in 15 mL of 90:10 n-hexane:IPAcontaining 0.1% DEA, and resulting solution was subjected to chiral HPLCpurification using Chiralpak®IA [250 mm×4.6 mm×5 μm] column, mobilephase 90:10 n-hexane:IPA (containing 0.1% DEA); flow rate: 1 mL/min].Eluted fractions of the two enantiomers were separately collected andeach of these fractions was concentrated to afford 40 mg (53%) ofenantiomer #1 of Example 65 (99.9% ee), and 55 mg (73%) of enantiomer #2of Example 65 (90.5% ee).

Enantiomer #1 of Example 65 (30 mg, 0.09 mmol) was dissolved in EtOH (1mL) and to this solution was added KOH (19.64 mg, 0.35 mmol). Theresulting mixture was stirred at room temperature for 30 min. To thereaction mixture was added water (10 mL). The mixture was extracted withethyl acetate (3×25 mL), and the combined organic phase was concentratedunder vacuum to afford 15 mg (57%) of(−)-1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol (Example9) as a colorless crystalline solid.

Similarly, enantiomer #2 of Example 65 (40 mg, 0.12 mmol) was dissolvedin EtOH (1 mL) and to this solution was added KOH (26.2 mg, 0.47 mmol).Following similar reaction and work up conditions as described above, 21mg (60%) of(+)-1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol (Example8) was obtained as a colorless crystalline solid.

The samples of Example 8 and Example 9 prepared by this method werecharacterized by chiral HPLC as follows: Example 8, Enantiomer #1,retention time 11.0 min; Example 9, Enantiomer #2, retention time 19.9min; consistent with the enantiomer samples obtained by direct chiralseparation of Example 7 as described above. Chiral HPLC conditions:Chiralpak IA (250 mm×4.6 mm×5 um), Mobile phase: n-hexane:EtOAc with0.1% DEA (60:40), Flow rate: 1.0 mL/min., sample preparation: 1 mg/2 mLof mobile phase.

Example 11 1-(5-(4-Fluorophenyl)pyrazin-2-yl)-1-(pyridin-4-yl)ethanol(synthetic method of Scheme 4)

Step 1: 2-Bromo-5-(4-fluorophenyl)pyrazine

To a solution of 2,5-dibromopyrazine (100 mg, 0.4 mmol) in toluene (6mL) and ethanol (3 mL) was added (4-fluorophenyl)boronic acid (29 mg,0.2 mmol) and 2M sodium carbonate solution (2.84 mL). The solution waspurged with argon for 15 min, Pd(PPh₃)₄ (4 mg, 0.004 mmol) was added,and the reaction mixture was purged with argon for 15 min. The resultingmixture was heated to 40° C. and stirred for 1 h. The reaction mixturewas concentrated, diluted with water (20 mL), and extracted with ethylacetate (2×100 mL). The combined extracts were washed with brinesolution (10 mL), and dried over Na₂SO₄ and concentration in vacuo. Thecrude product was purified by flash chromatography (60-120μ, 5% ethylacetate in hexane) to afford 2-bromo-5-(4-fluorophenyl)pyrazine asoff-white solid (60 mg, 57% yield). 1H NMR (400 MHz, DMSO-d₆): δ 9.08(s, 1H), 8.88 (s, 1H), 8.18-8.15 (m, 2H), 7.37 (dd, 2H); LC-MS m/zcalculated for [M+H]⁺ 252.97, found 253.0.

Step 2: 1-(5-(4-Fluorophenyl)pyrazin-2-yl)-1-(pyridin-4-yl)ethanol

2-bromo-5-(4-fluorophenyl)pyrazine (115 mg, 0.4 mmol) in THF (10 mL) wascooled to −78° C., 1.6 M n-BuLi in hexane (0.56 mL, 0.8 mmol) addedslowly at −78° C., the reaction mixture was stirred for 10 min at −78°C., and 1-(pyridin-4-yl)ethanone (54 mg, 0.4 mmol) in THF (3 mL) wasadded. The resulting mixture was stirred at −78° C. for 1 h. Thereaction mixture was quenched with saturated NH₄Cl solution (10 mL) andextracted with ethyl acetate (2×200 mL). The combined extracts werewashed with brine solution (20 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum to obtain crude product. The crude product waspurified by preparative TLC (mobile phase: 60% ethyl acetate in hexane)to afford 1-(5-(4-fluorophenyl)pyrazin-2-yl)-1-(pyridin-4-yl)ethanol asoff-white solid (32 mg, 24% yield) in 98.7% HPLC purity. 1H NMR (400MHz, DMSO-d₆): δ 9.13 (s, 1H), 8.93 (s, 1H), 8.48 (d, 2H), 8.16-8.13 (m,2H), 7.49 (d, 2H), 7.34 (t, 2H), 6.43 (s, 1H), 1.90 (s, 3H); LC-MS m/zcalculated for [M+H]⁺ 296.11, found 296.1.

Example 126′-(1-Hydroxy-1-(pyridin-4-yl)ethyl)-[3,3′-bipyridine]-6-carbonitrile(synthetic method of Scheme 1)

Step 1: 6′-Acetyl-[3,3′-bipyridine]-6-carbonitrile

To a stirred solution of 1-(5-bromopyridin-2-yl)ethanone (0.2 g, 1 mmol)in toluene (10 mL) and ethanol (5 mL) was added5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (0.46 g,2 mmol) and Pd(PPh₃)₄ (0.057 g, 0.05 mmol). The reaction mixture waspurged with argon for 5 min, 2M Na₂CO₃ solution (3.5 mL, 0.74 g, 7 mmol)was added, and the reaction mixture was stirred at 75-80° C. for 6 h.The reaction mixture was cooled to room temperature, quenched withsaturated sodium bicarbonate solution (2×100 mL), and extracted intoethyl acetate (2×100 mL). The organic layer was washed with brine andice-cold water (2×100 mL), dried over sodium sulfate, filtered andconcentrated under reduced pressure to obtain crude product. The crudeproduct was purified by column chromatography (100-200μ silica gel,using 15-16% ethyl acetate in hexane) to obtain6′-acetyl-[3,3′-bipyridine]-6-carbonitrile as white solid (0.18 g, 80%yield). 1H NMR (400 MHz, DMSO-d₆): δ 9.24 (dd, 1H), 9.20 (dd, 1H), 8.54(dd, 1H), 8.46 (dd, 1H), 8.23 (dd, 1H), 8.09 (dd, 1H), 2.68 (s, 3H);LC-MS m/z calculated for [M+H]⁺ 224.07, found 224.1.

Step 2:6′-(1-Hydroxy-1-(pyridin-4-yl)ethyl)-[3,3′-bipyridine]-6-carbonitrile

Using 4-iodo pyridine (0.22 g, 1.076 mmol), and6′-acetyl-[3,3′-bipyridine]-6-carbonitrile (0.12 g, 0.54 mmol) andprocedure described for example 7 and step 4, crude product wasobtained. The crude product was purified by preparative TLC (5% methanolin ethyl acetate) to obtain6′-(1-hydroxy-1-(pyridin-4-yl)ethyl)-[3,3′-bipyridine]-6-carbonitrile asoff-white solid (30 mg, 18% yield) in 98% HPLC purity. 1H NMR (400 MHz,DMSO-d₆): δ 9.12 (s, 1H), 8.94 (s, 1H), 8.46 (d, 2H), 8.38 (dd, 1H),8.23 (dd, 1H), 8.14 (d, 1H), 7.82 (d, 1H), 7.49 (d, 2H), 6.27 (s, 1H),1.9 (s, 3H); LC-MS m/z calculated for [M+H]⁺ 303.12, found 303.1.

Example 131-(5-(4-Fluorophenyl)thiazol-2-yl)-1-(pyridin-4-yl)propan-1-ol(synthetic method of Scheme 7)

Step 1: 5-(4-Fluorophenyl)thiazole

To a sealed tube containing a solution of thiazole (2 g, 23.53 mmol) inDMA (10 mL) was added potassium acetate (6.9 g, 70.58 mmol),1-fluoro-4-iodobenzene (15.6 g, 70.58 mmol), and palladium hydroxide\C(0.53 g, 2.35 mmol) under nitrogen. The reaction mixture was heated to145° C. and stirred for 16 h. The reaction mixture was cooled to roomtemperature and diluted with water (200 mL), filtered through Celite®reagent, and extracted with ethyl acetate (300 mL). The organic layerwas dried over sodium sulfate, filtered and concentrated under reducedpressure to obtain crude product. The crude product was purified bycolumn chromatography (100-200μ silica gel, eluting with 10% EtOAc andhexane) to afford 5-(4-fluorophenyl)thiazole (0.9 g, 22%). 1H NMR (400MHz, CDCl₃): δ 8.74 (s, 1H), 8.01 (s, 1H), 7.55 (t, 2H), 7.11 (t, 2H).

Step 2: 5-(4-Fluorophenyl)thiazole-2-carbaldehyde

A solution of 5-(4-fluorophenyl)thiazole (0.5 g, 2.78 mmol) and THF (40mL) was cooled to −78° C., 1.6 M n-BuLi in hexanes (0.7 mL, 8.36 mmol)was slowly added, the solution was stirred for 20 min and DMF in THF (20mL) was added. The reaction mixture was stirred at −78° C. for 2 h,quenched with saturated ammonium chloride solution and diluted withethyl acetate (150 mL). The organic layer was separated, washed withammonium chloride (3×150 mL) and followed by brine solution (2×100 mL).The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure to obtain crude product. The crudeproduct was purified by column chromatography (100-200μ silica gel and18% ethyl acetate in hexane) to obtain5-(4-fluorophenyl)thiazole-2-carbaldehyde as off-white solid (0.4 g, 69%yield). 1H NMR (400 MHz, DMSO-d₆): δ 9.91 (s, 1H), 8.63 (s, 1H),7.88-7.91 (m, 2H), 7.35 (t, 2H), LC-MS m/z calculated for [M+H]⁺ 208.02found 208.1.

Step 3: 1-(5-(4-Fluorophenyl)thiazol-2-yl)propan-1-ol

Using 5-(4-fluorophenyl)thiazole-2-carbaldehyde (0.12 g, 0.58 mmol) andEtMgBr (0.577 mL, 1.73 mmol) and following the procedure described forexample 7 and step 2, the crude compound was obtained and furtherpurified by column chromatography (using 100-200μ silica gel and 38%ethyl acetate and hexane) to give1-(5-(4-fluorophenyl)thiazol-2-yl)propan-1-ol as pale yellow liquid (0.1g, 73% yield). 1H NMR (400 MHz, DMSO-d₆): δ 8.01 (s, 1H), 7.68-7.65 (m,2H), 7.25 (t, 2H), 6.11 (d, 1H), 4.72-4.67 (m, 1H), 1.84 (m, 1H),1.88-1.67 (m, 1H), 0.91 (t, 3H); LC-MS m/z calculated for [M+H]⁺ 238.06,found 238.5.

Step 4: 1-(5-(4-Fluorophenyl)thiazol-2-yl)propan-1-one

1-(5-(4-fluorophenyl)thiazol-2-yl)propan-1-ol (0.05 g, 0.21 mmol) wasoxidized using the procedure described for example 7 and step 3 toprovide 1-(5-(4-fluorophenyl)thiazol-2-yl)propan-1-one after columnchromatography purification (100-200μ silica gel and 15% ethyl acetatein hexane) as off-white solid (40 mg, 81% yield). 1H NMR (400 MHz,DMSO-d₆): δ 8.49 (s, 1H), 7.89-7.85 (m, 2H), 7.35 (t, 2H), 3.13 (q, 2H),1.13 (t, 3H); LC-MS m/z calculated for [M+H]⁺ 236.05, found 236.1.

Step 5: 1-(5-(4-Fluorophenyl)thiazol-2-yl)-1-(pyridin-4-yl)propan-1-ol

Using 1-(5-(4-fluorophenyl)thiazol-2-yl)-1-(pyridin-4-yl)propan-1-ol(0.04 g, 0.17 mmol) and 4-iodopyridine (0.069 g, 0.34 mmol) andfollowing the procedure described for example 7 and step 4, crudecompound was obtained and was further purified by preparative TLC (5%methanol in dichloromethane) to give1-(5-(4-fluorophenyl)thiazol-2-yl)-1-(pyridin-4-yl)propan-1-ol (14 mg,10% yield) in 95% HPLC purity. 1H NMR (400 MHz, DMSO-d₆): δ 8.52-8.49(m, 2H), 8.05 (s, 1H), 7.65-7.62 (m, 2H), 7.56 (d, 2H), 7.23 (t, 2H),6.81 (br s, 1H), 2.34-2.24 (m, 2H), 0.77 (t, 3H); LC-MS m/z calculatedfor [M+H]⁺ 315.09, found 315.1.

Example 14 1-(5-(4-Fluorophenyl)thiazol-2-yl)-1-(pyridin-4-yl)ethanol(synthetic method of Scheme 3)

Step 1: 5-(4-Fluorophenyl)thiazole

Using 5-bromothiazole (1.0 g, 6.09 mmol) and (4-fluorophenyl)boronicacid (1.0 g, 7.31 mmol) and following the procedure described in example7 step 1, the title compound was obtained after purification by purifiedby Biotage IsoleraOne® column (10% ethyl acetate in hexane) as yellowviscous liquid (0.4 g, 36% yield). 1H NMR (400 MHz, DMSO-d₆): δ 9.05 (s,1H), 8.25 (s, 1H), 7.73-7.69 (m, 2H), 7.27 (t, 2H); LC-MS m/z calculatedfor [M+H]⁺ 180.02, found 180.1.

Step 2: 1-(5-(4-Fluorophenyl)thiazol-2-yl)-1-(pyridin-4-yl)ethanol

To a solution of 5-(4-fluorophenyl)thiazole (0.1 g, 0.558 mmol) in dryTHF (8 mL) at −78° C., was slowly added n-1.6 M BuLi in hexanes (0.7 mL,1.117 mmol), the reaction mixture was stirred for 30 minutes and1-(pyridin-4-yl)ethanone (0.13 mL, 1.117 mmol) in THF (8 mL) was added.The reaction mixture was stirred for 2 hours at −78° C., the reactionmixture quenched with saturated NH₄Cl solution (50 mL), extracted withEtOAc (2×50 mL), the organic layer washed with water (50 mL), dried overNa₂SO₄ and concentrated under reduced pressure to obtain crude product.The crude product was purified by preparative TLC (5% methanol indichloromethane) to give 1-(5-(4-fluorophenyl)thiazol-2-yl)-1-(pyridin-4-yl)ethanol as off-white solid (35 mg, 22%yield) in 99.6% HPLC purity. 1H NMR (400 MHz, DMSO-d₆): δ 8.50 (br s,1H), 8.03 (s, 1H), 7.66-7.63 (m, 2H), 7.53 (br s, 2H), 7.24 (t, 2H),6.99 (s, 1H), 1.89 (s, 3H); LC-MS m/z calculated for [M+H]⁺ 301.07,found 301.4.

Example 155-(5-(1-Hydroxy-1-(pyridin-4-yl)ethyl)thiophen-2-yl)-1-methyl-pyridin-2(1H)-one(synthetic method of Scheme 6)

Step 1: 5-Bromo-2-methoxypyridine

A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76 g,69.6 mmol) in MeOH (60 mL) was heated at 70° C. for 1 hour and thenallowed to cool to room temperature. The reaction mixture was dilutedwith water (50 mL) and extracted with EtOAc (2×100 mL). The combinedorganic layers were dried over Na₂SO₄ and concentrated under reducedpressure to give a pale yellow volatile oil (2.5 g, 58% yield). 1H NMR(400 MHz, DMSO-d₆): δ 8.26 (s, 1H), 7.87 (dd, 1H), 6.81 (d, 1H), 3.82(s, 3H).

Step 2: 5-Bromopyridin-2(1H)-one

5-bromo-2-methoxypyridine (2.5 g, 13.29 mmol) was dissolved in 6N HCl(30 mL). The solution was heated at 100° C. and stirred for 5 h. Thereaction mixture was cooled to 5° C. and the pH of the reaction mixturewas adjusted to 6.5 with 10% aqueous NaOH. The precipitate was collectedby filtration, washed with water (100 mL), and dried under vacuum toobtain 5-bromopyridin-2(1H)-one (1.5 g, 65% yield). 1H NMR (400 MHz,CDCl₃): δ 10.2-8.2 (br s, 1H) 7.52-7.49 (m, 2H), 6.51 (d, 1H); LC-MS m/zcalculated for [M+H]⁺ 173.95, found 173.8.

Step 3: 5-Bromo-1-methylpyridin-2(1H)-one

To a solution of 5-bromopyridin-2(1H)-one (0.18 g, 1.03 mmol) in DMF (5mL) was added iodomethane (0.2 mL, 3.1 mmol) and potassium carbonate(0.8 g, 6.2 mmol). The reaction mixture was stirred at room temperaturefor 2 h. The reaction mixture was then concentrated under reducedpressure, the residue dissolved in ethyl acetate (200 mL), washed withwater (50 mL) and brine solution. The organic layers were combined anddried over sodium sulfate, filtered and concentrated under vacuum toafford 5-bromo-1-methylpyridin-2(1H)-one [Albrecht, US PatentApplication Publication No. 2009/0318436] as yellow solid (40 mg, 21%).1H NMR (DMSO-d₆): δ 8.01 (d, 1H), 7.49 (dd, 1H), 6.34 (d, 1H), 3.38 (s,3H); LC-MS m/z calculated for [M+H]⁺ 187.96, found 188.2.

Step 4: 5-(5-Acetylthiophen-2-yl)-1-methylpyridin-2(1H)-one

To a solution of 5-bromo-1-methylpyridin-2(1H)-one (0.2 g, 1.06 mmol) in1,4-dioxane (5 mL) and water (2 mL), (5-acetylthiophen-2-yl)boronic acid(0.2 g, 1.27 mmol), tetrabutyl ammonium bromide (0.034 g, 0.16 mmol),K₂CO₃ (0.4 mL, 3.19 mmol) and Pd(PPh₃)₂Cl₂ (0.18 g, 1.59 mmol) wereadded under argon. The mixture was purged with argon for 10 min andheated to 100° C. for 1 h. The reaction mixture was filtered throughCelite® reagent, the filtrate concentrated, the residue extracted withEtOAc (2×100 mL), and washed with water (100 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated under reduced pressure toobtain crude product. The crude product was purified by BiotageIsoleraOne® column purifier (80% ethyl acetate in hexane) and obtainedas yellow viscous liquid (0.15 g, 62% yield). 1H NMR (400 MHz, CDCl₃): δ7.69-7.58 (m, 3H), 7.08 (d, 1H), 6.65 (d, 1H), 3.61 (s, 3H), 2.54 (s,3H); LC-MS m/z calculated for [M+H]⁺ 234.05, found 234.1.

Step 5:5-(5-(1-Hydroxy-1-(pyridin-4-yl)ethyl)thiophen-2-yl)-1-methylpyridin-2(1H)-one

Using 5-(5-acetylthiophen-2-yl)-1-methylpyridin-2(1H)-one (0.07 g, 0.3mmol), 4-iodopyridine (0.12 g, 0.6 mmol), and the procedure describedfor example 7 and step 4, crude compound was obtained and furtherpurified by preparative TLC (5% methanol in dichloromethane) to give5-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)thiophen-2-yl)-1-methylpyridin-2(1H)-oneas off-white solid (0.02 g, 21% yield) in 99.8% HPLC purity. 1H NMR (400MHz, DMSO-d₆): δ 8.48 (d, 2H), 7.97 (d, 1H), 7.65 (dd, 1H), 7.45-7.44(t, 2H), 7.07 (d, 1H), 6.94 (d, 1H), 6.41-6.38 (m, 2H), 3.42 (s, 3H),1.85 (s, 3H); LC-MS m/z calculated for [M+H]⁺ 313.09, found 313.1.

Examples 16 & 17 Enantiomer #1 and Enantiomer #2 of5-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)thiophen-2-yl)-1-methylpyridin-2(1H)-one

Racemic5-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)thiophen-2-yl)-1-methyl-pyridin-2(1H)-one(530 mg) was subjected to chiral HPLC purification using Chiralpak® IC[250 mm×4.6 mm×5 μm column, mobile phase: n-heptane:ethanol with 0.1%DEA (50:50); flow rate: 1 mL/min] to afford about 150 mg (56% recovery)(+)-5-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)thiophen-2-yl)-1-methylpyridin-2(1H)-one(Enantiomer #1; [α]_(D) ²⁵ +68.8 (c 1.0, MeOH)) and 150 mg (56%recovery) of(−)-5-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)thiophen-2-yl)-1-methylpyridin-2(1H)-one(Enantiomer #2; [α]_(D) ²⁵ −65.7 (c 1.0, MeOH)), each enantiomerisolated with 99.9% ee. For each enantiomer: 1H NMR (400 MHz, DMSO-d₆):δ 8.48 (d, 2H), 7.98 (d, 1H), 7.66 (dd, 1H), 7.45 (d, 2H), 7.07 (d, 1H),6.95 (d, 1H), 6.41 (s, 1H), 6.39 (s, 1H), 3.42 (s, 3H), 1.86 (s, 3H);LC-MS m/z calculated for [M+H]⁺ 313.09, found 313.6.

Example 181-(2-(1H-Pyrazol-4-yl)thiazol-5-yl)-1-(pyridin-4-yl)propan-1-ol

A. Preparation A According to the Synthetic Method of Schemes 1 and 2Step 1: 2-(1H-Pyrazol-4-yl)thiazole-5-carbaldehyde

To a solution of 2-bromothiazole-5-carbaldehyde (500 mg, 2.6 mmol) intoluene (15 mL) and ethanol (7 mL) was added4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (606 mg, 3.1mmol), 2M sodium carbonate solution (7.3 mL) and Pd(PPh₃)₄ (30 mg, 0.02mmol). The reaction mixture was purged with argon for 15 min and theresulting mixture was heated at 70° C. for 4 h. The reaction mixture wasconcentrated, diluted with water (100 mL), and extracted with ethylacetate (2×200 mL). The combined extracts were washed with brinesolution (20 mL), dried over Na₂SO₄, filtered and concentrated to undervacuum to obtain crude product. The crude product was purified by flashchromatography (60-120μ; 50% ethyl acetate in hexane) to afford2-(1H-pyrazol-4-yl)thiazole-5-carbaldehyde as yellow solid (250 mg, 54%yield). 1H NMR (400 MHz, DMSO-d₆): δ 13.49 (br s, 1H), 10.00 (s, 1H),8.61 (s, 1H), 8.55 (s, 1H), 8.09 (s, 1H); LC-MS m/z calculated for[M+H]⁺ 180.02, found 180.1.

Step 2: 1-(2-(1H-Pyrazol-4-yl)thiazol-5-yl)propan-1-ol

A solution of 2-(1H-pyrazol-4-yl)thiazole-5-carbaldehyde (245 mg, 1.3mmol) in THF (15 mL) was cooled to 0° C., a 3M solution of ethylmagnesium bromide in diethyl ether (0.9 mL, 2.7 mmol) slowly added at 0°C., and the reaction mixture stirred for 2 hours at 0° C. The reactionmixture was quenched with saturated NH₄Cl solution (10 mL) and extractedwith ethyl acetate (2×200 mL). The combined extracts were washed withbrine solution (20 mL), dried over Na₂SO₄, filtered and the organicsolvent was concentrated under reduced pressure to obtain crude product.The crude product was purified by flash chromatography (60-120μ; 3%methanol in dichloromethane) to afford1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)propan-1-ol as pale yellow liquid(180 mg, 63% yield). 1H NMR (400 MHz, DMSO-d₆): δ 13.19 (br s, 1H), 8.25(s, 1H), 7.88 (s, 1H), 7.51 (s, 1H), 5.59 (d, 1H), 4.71 (q, 1H),1.97-1.64 (m, 2H), 0.86 (t, 3H); LC-MS m/z calculated for [M+H]⁺ 210.06,found 210.1.

Step 3: 1-(2-(1H-Pyrazol-4-yl)thiazol-5-yl)-1-(pyridin-4-yl)propan-1-ol

A solution of 1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)propan-1-ol (175 mg,0.83 mmol) in dichloromethane (15 mL) was cooled to 0° C. add DessMartinPeriodinane (1.06 g, 2.51 mmol) was slowly added at 0° C. The reactionmixture was allowed to stir at room temperature for about 3 h, quenchedwith saturated NaHCO₃ solution (10 mL), followed by sodium thiosulfatesolution (5 mL), and extracted with dichloromethane (2×200 mL). Thecombined extracts were washed with brine solution (10 mL), the organiclayer was dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was subjected to a small filter column, theproduct 1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)propan-1-one (140 mg)confirmed by LC-MS and then used for the next step. LC-MS m/z calculatedfor [M+H]⁺ 208.05, found 208.1

A solution of 4-iodopyridine (133 mg, 0.65 mmol) in THF (15 mL) wascooled to −78° C., 1.6 M n-BuLi in hexane (0.81 mL, 1.3 mmol) slowlyadded at −78° C., the reaction mixture stirred for 20 min at −78° C.,and 1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)propan-1-one (135 mg, 0.65 mmol)in THF (5 mL) added. The resulting mixture was stirred at −78° C. for 2h. The reaction mixture was quenched with saturated NH₄Cl solution (10mL) and extracted with ethyl acetate (2×250 mL). The combined extractswere washed with brine solution (10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to obtain crude product. The crudeproduct was purified by preparative TLC (mobile phase: 5% methanol indichloromethane) to afford1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)-1-(pyridin-4-yl)propan-1-ol as paleyellow liquid (13 mg, 5% yield) in 99.4% HPLC purity. 1H NMR (400 MHz,DMSO-d₆): δ 13.19 (br s, 1H), 8.51 (d, 2H), 8.24 (br s, 1H), 7.87 (br s,1H), 7.65 (s, 1H), 7.45 (d, 2H), 6.29 (s, 1H), 2.32-2.23 (m, 2H), 0.77(t, 3H); LC-MS m/z calculated for [M+H]⁺287.09, found 287.1

B. Preparation B According to the Synthetic Method of Scheme 3 Step 1:2-(1H-Pyrazol-4-yl)thiazole

To a solution of 2-bromothiazole (1 g, 6 mmol) in toluene (20 mL) andethanol (10 mL) was added4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.41 g, 7.3mmol), 2 M sodium carbonate solution (17.3 mL) and Pd(PPh₃)₄ (7 mg, 0.06mmol). The reaction mixture was purged with argon for 15 min. Theresulting mixture was heated at 70° C. for 4 h. The reaction mixture wasconcentrated and diluted with water (100 mL), extracted with ethylacetate (2×200 mL). The combined extracts were washed with brinesolution (20 mL), the organic solvent was dried over Na₂SO₄, filteredand concentrated under reduced pressure to obtain crude product. Thecrude product was purified by flash chromatography (60-120μ; 50% ethylacetate in hexane) to afford racemic 2-(1H-pyrazol-4-yl)thiazole asbrown liquid (520 mg, 56% yield). 1H NMR (400 MHz, DMSO-d₆): δ 13.22 (brs, 1H), 8.30 (s, 1H), 7.93 (s, 1H), 7.73 (s, 1H), 7.55 (d, 1H); LC-MSm/z calculated for [M+H]⁺ 152.02, found 152.1.

Step 2: 1-(2-(1H-Pyrazol-4-yl)thiazol-5-yl)-1-(pyridin-4-yl)propan-1-ol

To a stirred solution of diisopropylamine (0.28 mL, 1.9 mmol) in THF (10mL) at −60° C. was added n-BuLi (1.6 M, 2.48 mL) slowly. The reactionmixture was stirred for 30 min at −10° C., cooled to −78° C., and asolution 2-(1H-pyrazol-4-yl)thiazole (200 mg, 1.3 mmol) in THF (5 mL)added dropwise for 30 minutes. 4-Acetyl pyridine (0.07 mL, 0.000674mmol) in THF (2 mL) was then added and the reaction mixture stirred foradditional 1 hour at −78° C. The work up was done as described inExample 23, Step 2, to obtain crude product. The crude product waspurified by preparative TLC (mobile phase: 70% ethyl acetate in hexane)to give racemic1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)-1-(pyridin-4-yl)propan-1-ol as paleyellow solid (134 mg, 35% yield) in 99% HPLC purity. 1H NMR (400 MHz,DMSO-d₆): δ 13.18 (br s, 1H), 8.50 (d, 2H), 8.22 (br s, 1H), 7.85 (br s,1H), 7.63 (s, 1H), 7.43 (d, 2H), 6.28 (s, 1H), 2.32-2.24 (m, 2H), 0.75(t, 3H); LC-MS m/z calculated for [M+H]⁺ 287.09, found 287.1.

Examples 19 and 20 Enantiomer #1 and Enantiomer #2 of1-(2-(1H-Pyrazol-4-yl)thiazol-5-yl)-1-(pyridin-4-yl)propan-1-ol

Racemic 1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)-1-(pyridin-4-yl)propan-1-ol(150 mg) was subjected to chiral HPLC purification using Chiralpak® IC[250 mm×4.6 mm×5μ column, mobile phase: n-heptane:ethanol with 0.1% DEA(50:50); flow rate: 1 mL/min] to afford 63 mg (84% recovery) of(−)-1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)-1-(pyridin-4-yl)propan-1-ol(Enantiomer #1; [α]_(D) ²⁵ −15.5 (c 1.0, MeOH)) and 63 mg (84% recovery)of (+)-1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)-1-(pyridin-4-yl)propan-1-ol(Enantiomer #2; [α]_(D) ²⁵ +15.7 (c 1.0, MeOH)), each enantiomerisolated with >99% ee. For each enantiomer: 1H NMR (400 MHz, DMSO-d₆): δ13.17 (br s, 1H), 8.50 (d, 2H), 8.22 (br s, 1H), 7.85 (br s, 1H), 7.63(s, 1H), 7.43 (d, 2H), 6.27 (s, 1H), 2.30-2.22 (m, 2H), 0.75 (t, 3H);LC-MS m/z calculated for [M+H]⁺ 287.09, found 287.1

Example 211-(5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)-1-(pyridin-4-yl)propan-1-ol(synthetic method of Schemes 9, 2, and 1)

Step 1: (5-bromo-1,3,4-thiadiazol-2-yl)methanol

A solution of ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (3.0 g,12.65 mmol) [prepared as described in Jean-Philippe, InternationalPatent Publication No. WO-2011/011872] in methanol (50 mL) was cooled to0° C. and sodium borohydride (1.405 g, 37.97 mmol) slowly added and thereaction mixture was allowed to stir for 16 hours at room temperature.The reaction mixture was quenched with acetic acid (3 mL), extractedwith ethyl acetate (200 mL), and the organic layer washed with sodiumbicarbonate solution (20 mL) and then brine solution (10 mL). Theorganic layer was separated, dried over sodium sulfate and evaporatedunder reduced pressure to obtain crude product. The crude product waspurified by Biotage IsoleraOne® column (using 25% ethyl acetate andhexane) to give (5-bromo-1,3,4-thiadiazol-2-yl)methanol as white solid(1.8 g, 73% Yield). ¹H NMR (400 MHz, DMSO-d₆): δ 6.31 (t, 3H), 4.85 (d,2H); LC-MS m/z calculated for [M+H]⁺ 194.9, found 195.0.

Step 2: (5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methanol

To a solution of (5-bromo-1,3,4-thiadiazol-2-yl)methanol (1.2 g, 6.153mmol) in toluene (40 mL) and ethanol (40 mL) was added 4-fluorophenylboronic acid (1.026 g, 7.384 mmol) and 2 M solution of aqueous Na₂CO₃.The reaction mixture was degassed with argon, Pd(PPh₃)₄ (0.354 g, 0.355mmol) was added, the reaction mixture again degassed with argon for 10min, and the mixture heated to 100° C. for 2 h. The reaction mixture wasevaporated under vacuum to remove the ethanol, diluted with water (50mL), extracted with ethyl acetate (200 mL), dried over sodium sulfate,filtered and evaporated under reduced pressure to obtain crude product.The crude product was purified by Biotage IsoleraOne® column (using 30%ethyl acetate and hexane) to give(5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)methanol as pale yellow solid(0.85 g, 65% yield); LC-MS m/z calculated for [M+H]⁺ 211.03, found211.1.

Step 3: 5-(4-fluorophenyl)-1,3,4-thiadiazole-2-carbaldehyde

To a solution of 5-(4-fluorophenyl)-1,3,4-thiadiazole-2-yl)methanol(0.85 g, 4.0476 mmol) in dichloromethane (30 mL) at 0° C. was addedDessMartin Periodinane (3.4 g, 8.095 mmol) slowly. The reaction mixturewas allowed to warm to room temperature for 3 hours and saturated sodiumbicarbonate solution (20 mL) and sodium thiosulfate (2 g) were added.The reaction mixture was extracted with ethyl acetate (200 mL), driedover sodium sulfate, filtered and evaporated under reduced pressure toobtain crude product. The crude compound was purified by flash columnchromatography (using 20% ethyl acetate in hexane) to obtain5-(4-fluorophenyl)-1,3,4-thiadiazole-2-carbaldehyde as white solid (0.45g, 53% yield). 1H NMR (400 MHz, DMSO-d₆): δ 10.17 (s, 1H), 8.19 (q, 2H),7.45 (t, 2H); LC-MS m/z calculated for [M+H]⁺ 209.01, found 209.1.

Step 4: 1-(5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol

To a solution of 5-(4-fluorophenyl)-1,3,4-thiadiazole-2-carbaldehyde(0.2 g, 0.961 g mmol) in THF (8 mL) was added ethyl magnesium bromide indiethyl ether (3.0 M; 0.96 mL, 2.88 mmol) at 0° C., the reaction mixturewas allowed to warm to room temperature and the mixture then stirred for2 h. The reaction mixture was quenched with saturated ammonium chloridesolution (15 mL) and water (15 mL), extracted with ethyl acetate (100mL), dried over sodium sulfate and concentrated under reduced pressureto afford 1-(5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol asyellow solid (0.1 g, 45% yield). 1H NMR (400 MHz, DMSO-d₆): δ 8.0-8.03(m, 1H), 7.39-7.35 (m, 2H), 6.36 (d, 1H), 4.92-4.89 (m, 1H), 1.89-1.78(m, 2H), 0.95 (t, 3H); LC-MS m/z calculated for [M+H]⁺ 239.06, found239.1.

Step 5: 1-(5-(4-fluorophenyl-1,3,4-thiadizol-2-yl) propan-1-one

1-(5-(4-fluorophenyl)-1,3,4-thiadiazole-2-yl)propan-1-ol (0.210 g, 0.882mmol) was oxidized using Dess-Martin Periodinane using the proceduredescribed in step 3 to provide1-(5-(4-fluorophenyl-1,3,4-thiadizol-2-yl)propan-1-one as yellow solid(0.1 g, 50% yield). 1H NMR (400 MHz, DMSO-d₆): δ 8.04 (m, 2H), 7.25-7.19(m, 2H), 3.30 (q, 2H), 1.31-1.29 (t, 3H); LC-MS m/z calculated for[M+H]⁺ 237.04, found 237.1.

Step 6:1-(5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)-1-(pyridin-4-yl)propan-1-ol

To a solution of 4-iodo pyridine (0.142 g, 0.635 mmol) in THF (12 mL) at−78° C. was added n-BuLi in hexane (1.6 M, 0.582 mL, 0.8474 mmol) andthe mixture stirred for 30 min. A solution of1-(5-(4-fluorophenyl)-1,3,4-thiadiazole-2-yl)propan-1-one (0.1 g, 0.4237mmol) in THF (8 mL) was added to above solution at −78° C. and themixture stirred for 1 hour at −78° C. The reaction mixture was quenchedwith saturated ammonium chloride solution (20 mL) and diluted with water(25 mL). The reaction mixture was extracted with ethyl acetate (200 mL),dried over sodium sulfate and concentrated under reduced pressure toobtain crude product. The crude compound was purified by preparative TLC(using 5% methanol and dichloromethane) to afford1-(5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)-1-(pyridin-4-yl)propan-1-olas white solid (22 mg, 17% yield). 1H NMR (400 MHz, DMSO-d₆): δ 8.55 (d,2H), 8.0-7.96 (m, 2H), 7.56 (d, 2H), 7.35 (t, 2H), 7.06 (s, 1H),2.40-2.30 (m, 2H), 0.80 (t, 3H); LC-MS m/z calculated for [M+H]⁺ 316.08,found 316.1.

Example 221-(2-(6-Fluoropyridin-3-yl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol(synthetic method of Scheme 6)

Step 1: 2-(6-Fluoropyridin-3-yl)thiazole

To a solution of 5-bromo-2-fluoropyridine (0.5 g, 2.857 mmol) in DMF (6mL), 2-(tributylstannyl)thiazole (1.3 mL, 4.285 mmol) and Pd(PPh₃)₂Cl₂(0.2 mg, 0.2857 mmol) were added under argon. The mixture was degassedwith argon for 10 min and heated to 100° C. for 30 min. The reactionmixture was filtered through Celite® reagent and the filtrate wasdiluted with EtOAc (2×100 mL) and water (100 mL). The organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated under reducedpressure to obtain crude product. The crude product was purified byBiotage IsoleraOne® column (5% ethyl acetate in hexane) to obtain2-(6-fluoropyridin-3-yl) thiazole as off-white solid (0.4 g, 80% yield).1H NMR (400 MHz, DMSO-d₆): δ 8.80 (s, 1H), 8.52-8.47 (m, 1H), 7.98 (d,1H), 7.87 (d, 1H), 7.33 (dd, 1H); LC-MS m/z calculated for [M+H]⁺181.02, found 180.8.

Step 2: 1-(2-(6-Fluoropyridin-3-yl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol

To a solution of diisopropylamine (0.12 mL, 0.833 mmol) in dry THF (5mL) was added n-BuLi in hexanes (1.6M, 0.7 mL, 1.111 mmol) slowly at−78° C. The mixture was stirred for 30 min,2-(6-fluoropyridin-3-yl)thiazole (0.1 g, 0.555 mmol) in THF (5.0 mL) at−78° C. added, and the mixture stirred for 30 min. A solution of1-(pyridin-4-yl)ethanone (0.09 mL, 0.833 mmol) in THF (5.0 mL) was addedto reaction mixture, stirred for 2 hours at −78° C. The reaction mixturewas quenched with saturated NH₄Cl (50 mL) solution and extracted withEtOAc (3×50 mL). The organic layer was washed with water (2×50 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure toobtain crude product. The crude product was purified by preparative TLC(3% methanol in dichloromethane) to obtain1-(2-(6-fluoropyridin-3-yl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol asoff-white solid (0.035 g, 22% yield) in 99.7% HPLC purity. 1H NMR (400MHz, DMSO-d₆): δ 8.31 (s, 1H), 8.21 (d, 2H), 7.79 (d, 1H), 7.71 (d, 1H),7.67 (s, 1H), 7.11 (s, 1H), 6.91 (d 2H), 1.83 (s, 3H); LC-MS m/zcalculated for [M+H]⁺ 302.07, found 302.1.

Example 23 1-(2-(4-Fluorophenyl)oxazol-5-yl)-1-(pyridin-4-yl)ethanol(synthetic method of Scheme 7)

Step 1: 2-(4-Fluorophenyl)oxazole

A solution of 1-fluoro-4-iodobenzene (1 g, 0.0144 mmol) in DMF (15 mL)was purged with argon, and oxazole (6.4 g/3.3 mL, 0.02898 mmol), copperiodide (5.5 g, 0.02898 mmol) and palladium (II) acetate (0.15 g,0.000724 mmol) was added. The reaction mixture was purged with argon for5 min and refluxed under argon for 12 h. The solution was cooled to roomtemperature and diluted with ice cold water (100 mL). The reactionmixture was extracted with ethyl acetate (200 mL) and filtered throughCelite® reagent. The organic solvent was dried with sodium sulfate,filtered and the solvent was removed under reduced pressure to obtaincrude product. The crude product was purified by Biotage IsoleraOne®column using a 25 g column (7% ethyl acetate in hexane) to give2-(4-fluorophenyl)oxazole (0.6 g, 26%) as yellow liquid. 1H NMR (400MHz, DMSO-d₆): δ 8.19 (s, 1H), 8.03-7.99 (m, 2H), 7.34 (t, 3H); LC-MSm/z calculated for [M+H]⁺ 164.05, found 164.1.

Step 2: 1-(2-(4-Fluorophenyl)oxazol-5-yl)-1-(pyridin-4-yl)ethanol

To a stirred solution of DIPA (0.13 mL, 0.00092 mmol) in THF (7 mL) at−78° C. was added n-BuLi (0.76 mL, 0.001226 mmol). The mixture wasallowed to stir at 0° C. for 30 min, was again cooled to −78° C., andthen a solution of 2-(4-fluorophenyl)oxazole (0.1 g, 0.000613 mmol) inTHF (2 mL) was added dropwise during 30 min. 4-Acetyl pyridine (0.07 mL,0.000674 mmol) in THF (2 mL) was then added, the reaction mixture wasstirred for an additional 1 hour at −78° C., quenched with saturatedammonium chloride (2 mL), diluted with water (10 mL), and extracted withethyl acetate (20 mL). The organic layer was dried with sodium sulfate,filtered and the solvent was concentrated under reduced pressure toobtain crude product. The crude product was purified by silica gelchromatography (200-400 mesh, 2% of methanol in dichloromethane) to give1-(2-(4-fluorophenyl)oxazol-5-yl)-1-(pyridin-4-yl)ethanol (0.14 g, 82%)as white solid in 98.5% HPLC purity. 1H NMR (400 MHz, DMSO-d₆): δ 8.53(d, 2H), 7.95-7.91 (m, 2H), 7.45 (d, 2H), 7.32 (t, 2H), 7.14 (d, 1H),6.38 (s, 1H), 1.81 (s, 3H); LC-MS m/z calculated for [M+H]⁺ 285.10,found 285.1.

Example 241-(2-(4-Fluorophenyl)thiazol-5-yl)-2-methyl-1-(pyridin-4-yl)propan-1-ol(synthetic method of Scheme 3)

Step 1: 2-(4-Fluorophenyl)thiazole

To a stirred solution of (4-fluorophenyl)boronic acid (10 g, 60.9 mmol)in toluene (70 mL) and ethanol (200 mL) was added 2-bromothiazole (12.7g, 91.4 mmol) and Na₂CO₃ (2M, 100 mL, 19.39 g). The reaction mixture waspurged with argon for 45 min, Pd(PPh₃)₄ (3.5 g, 3.04 mmol) added, andthe mixture stirred at 95° C. for 5 h. The reaction mixture was cooledto room temperature, quenched with saturated sodium bicarbonate solution(2×100 mL), and extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with ice-cold water (2×100 mL), followed bybrine solution (50 mL). The organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure to obtain crudeproduct. The crude product was purified by column chromatography(100-200 mesh silica gel; using 10% ethyl acetate in hexane) to obtain2-(4-fluorophenyl)thiazole as white solid (9.0 g, 82% yield). 1H NMR(400 MHz, DMSO-d₆): δ 7.98 (dd, 2H), 7.88 (d, 1H); 7.91 (d, 1H), 7.88(d, 1H), 7.31 (t, 2H); LC-MS m/z calculated for [M+H]⁺ 180.02 found179.91.

Step 2: (2-(4-Fluorophenyl)thiazol-5-yl)(pyridin-4-yl)methanol

To a solution of diisopropylamine (0.55 mL, 3.9 mmol) in dry THF (10 mL)at −78° C. was added n-BuLi (2.4 mL, 3.9 mmol) dropwise, and then themixture was stirred for 30 min to produce LDA. A solution of2-(4-fluorophenyl)thiazole (0.5 g, 2.79 mmol) in dry THF (10 mL) at −78°C. was added dropwise to the above LDA solution, and the mixture wasstirred for 30 min. To this reaction mixture was addedisonicotinaldehyde (0.298 g, 2.79 mmol) dropwise and the mixture wasstirred for 1 hour at −78° C. The reaction was quenched with ammoniumchloride solution (10 mL), extracted with ethyl acetate (2×20 mL),washed with brine solution (20 mL), dried over sodium sulfate,concentrated under reduced pressure and purified by silica gel columnchromatography (100-200 mesh silica gel; using 10% MeOH in DCM) toobtain 2-(4-fluorophenyl)thiazol-5-yl)(pyridin-4-yl)methanol (0.6 g, 75%yield). 1H NMR (400 MHz, DMSO-d₆): δ 8.56 (d, 2H), 7.91 (dd, 2H), 7.79(s, 1H), 7.44 (d, 2H), 7.28 (ds, 2H), 6.71 (d, 1H), 6.12 (d, 1H); LC-MSm/z calculated for [M+H]⁺ 287.06 found 287.02.

Example 255-(2-(4-fluorophenyl)thiazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-5-ol(synthetic method of Scheme 3)

Step 1: 2-(4-fluorophenyl)thiazole

To a stirred solution of (4-fluorophenyl)boronic acid (10 g, 60.9 mmol)in toluene (70 mL) and ethanol (200 mL) was added 2-bromothiazole (12.7g, 91.4 mmol), followed by Pd(PPh₃)₄ (3.5 g, 3.04 mmol). The reactionmixture was purged with argon for 20 min, Na₂CO₃ solution (2M, 100 mL,19.39 g) added, and the reaction mixture stirred at 95° C. for 5 h. Thereaction mixture was cooled to room temperature, quenched with saturatedsodium bicarbonate solution (2×100 mL), and extracted with ethyl acetate(2×100 mL). The combined organic layer was washed with ice-cold water(2×100 mL) followed by brine solution, dried over sodium sulfate,filtered and concentrated under reduced pressure to obtained crudeproduct. The crude product was purified by column chromatography(100-200 mesh silica gel) using 10% ethyl acetate in hexane to obtain2-(4-fluorophenyl)thiazole as white solid (9.0 g, 82% yield). 1H NMR(400 MHz, DMSO): 7.98 (dd, 2H, J=6.8 & 14.0 Hz), 7.88 (d, 1H, J=4.8 Hz),7.91 (d, 1H, J=2.8 Hz), 7.88 (d, 1H, J=4.8 Hz), 7.31 (t, 2H, J=8.8 &17.2 Hz).

Step 2:5-(2-(4-fluorophenyl)thiazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-5-ol

To a solution of DIPA (0.424 g, 4.2 mmol) in dry THF at −78° C. wasadded n-BuLi (0.268 g, 4.2 mmol) dropwise at −78° C., and the mixturewas stirred for 30 min to produce LDA. A solution of2-(4-fluorophenyl)thiazole (0.510 g, 2.8 mmol) in dry THF at −78° C. wasthen added to the above LDA solution. 7,8-Dihydroisoquinolin-5(6H)-one(0.419 g, 2.8 mmol) [prepared as described in Vanotti, InternationalPatent Publication No. WO-2008/065054] was added dropwise to thereaction mixture, which was then stirred for 20 min at −78° C. Aftercompletion of the reaction, the reaction was quenched with saturatedammonium chloride, extracted with ethyl acetate (3×30 mL), washed withwater followed by brine, dried over sodium sulfate, and concentratedunder reduced pressure. The crude solid was purified by washing with themixture of MeOH and ether, followed by filtering resulted in5-(2-(4-fluorophenyl)thiazol-5-yl)-5,6,7,8-tetrahydroisoquinolin-5-ol(0.42 g, 45% yield). 1H NMR (400 MHz, DMSO-d₆): δ 1.67 (m, 1H), 1.97 (m,1H), 2.16 (t, 2H), 2.80 (t, 2H), 6.50 (s, 1H), 7.26 (s, 1H), 7.29 (m,3H), 7.92 (m, 2H), 8.36 (m, 1H), 8.41 (s, 1H); LC-MS m/z calculated for[M+H]⁺ 327.09, found 327.1.

Example 261-(Pyridin-4-yl)-1-(2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)ethanol(synthetic method of Scheme 3)

Step 1: 2-(4-(Trifluoromethyl)phenyl)thiazole

Using (4-(trifluoromethyl)phenyl)boronic acid (0.5 g, 3.06 mmol) and2-bromo thiazole (1.1 g, 61.3 mmol) and following the proceduredescribed in Example 7, Step 1, the title compound was obtained afterpurification by flash chromatography (60-120 mesh, 2% ethyl acetate inhexane) as white solid (0.5 g, 83% Yield). 1H NMR (400 MHz, DMSO-d₆): δ8.15 (d, 2H), 8.00 (d, 1H), 7.90 (d, 1H), 7.85 (d, 2H); LC-MS m/zcalculated for [M+H]⁺ 230.02, found 230.1.

Step 2:1-(Pyridin-4-yl)-1-(2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)ethanol

To a stirred solution of DIPA (0.09 mL, 0.000655 mmol) in THF (7 mL) at−78° C. was added n-BuLi (0.54 mL, 0.000873 mmol) and the mixturestirred at 0° C. for 30 min. After the reaction mixture was cooled to−78° C., a solution of 2-(4-(trifluoromethyl)phenyl)thiazole (0.1 g,0.000436 mmol) in THF (2 mL) was added dropwise over 30 min.1-(Pyridin-4-yl)ethanone (0.05 mL, 0.000480 mmol) in THF (2 mL) was thenadded and the reaction mixture was stirred for an additional 1 hour at−78° C. The work up and purification was done as described in Example23, Step 2, to provide1-(pyridin-4-yl)-1-(2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)ethanol(0.12 g, 80%) as off-white solid in 99% HPLC purity. 1H NMR (400 MHz,DMSO-d₆): δ 8.52 (dd, 2H), 8.07 (d, 2H), 7.90 (s, 1H), 7.80 (d, 2H),7.50 (dd, 2H), 6.71 (s, 1H), 1.94 (s, 3H); LC-MS m/z calculated for[M+H]⁺ 351.07, found 351.1.

Example 28 1-(2-(4-Chlorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol(synthetic method of Scheme 3)

Step 1: 2-(4-Chlorophenyl)thiazole

Using 2-bromothiazole (0.5 g, 3.05 mmol) and (4-chlorophenyl)boronicacid (0.57 g, 3.65 mmol) and following the procedure described inExample 7, Step 1, the title compound was obtained after purification bycolumn chromatography (15% ethyl acetate in hexane) as colorless viscousliquid (0.5 g, 80% yield). 1H NMR (400 MHz, DMSO-d₆): δ 7.95 (d, 2H),7.92 (d, 1H), 7.80 (d, 1H), 7.55 (d, 2H); LC-MS m/z calculated for[M+H]⁺ 195.99, found 195.9.

Step 2: 1-(2-(4-Chlorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol

To a solution of diisopropylamine (0.2 mL, 1.538 mmol) in dry THF (5mL), was added 1.6M n-BuLi in hexanes (0.96 mL, 1.538 mmol) slowly at−78° C. The reaction mixture was stirred for 30 min,2-(4-chlorophenyl)thiazole (0.2 g, 1.025 mmol) in THF (10.0 mL) added,the mixture stirred for 30 min, a solution of 1-(pyridin-4-yl)ethanone(0.17 mL, 1.538 mmol) in THF (5.0 mL) added, and the mixture was stirredfor 2 hours at −78° C. The reaction mixture was quenched with saturatedNH₄Cl (50 mL) solution and extracted with EtOAc (2×100 mL). The organiclayer was washed with water (2×50 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to obtain crude product. The crudeproduct was purified by column chromatography (1% methanol indichloromethane) to obtain1-(2-(4-chlorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol as off-whitesolid (0.1 g, 31% yield) in 99.9% HPLC purity. 1H NMR (400 MHz,DMSO-d₆): δ 8.51 (d, 2H), 7.87 (d, 2H), 7.82 (s, 1H), 7.51-7.47 (m, 4H),6.66 (s, 1H), 1.92 (s, 3H); LC-MS m/z calculated for [M+H]⁺ 317.04,found 317.4.

Example 291-(5-(4-Fluorophenyl)-1,2,4-oxadiazol-3-yl)-1-(pyridin-4-yl)ethanol(synthetic method of Schemes 10A and 1)

Step 1: N,2-dihydroxyacetimidamide

To a solution of hydroxylamine hydrochloride (5 g, 72.4 mmol) in ethanol(70 mL) was added NaOH (3 g, 76.0 mmol) and the reaction stirredovernight at room temperature. The reaction was filtered,2-hydroxypropionitrile was added to the filtrate and the reactionstirred for 3 hours at room temperature. After completion, the reactionwas concentrated under reduced pressure to obtainN,2-dihydroxyacetimidamide as white solid (2.7 g, 36% yield). LC-MS m/zcalculated for [M+H]⁺ 105.06, found 105.0.

Step 2: 1-(5-(4-Fluorophenyl)-1,2,4-oxadiazol-3-yl)ethanol

To a solution of N,2-dihydroxyacetimidamide (2.7 g, 26.4 mmol) inpyridine (20 mL) was added dropwise 4-fluorobenzoyl chloride (3 g, 18.9mmol) in DCM (30 mL) at 0° C. to 10° C. The reaction was stirred for 6hours at room temperature and the solid was filtered and washed with DCM(50 mL). The solid was dissolved in ethanol and the solution refluxedfor 16 hours at 85° C. The mixture was evaporated under reducedpressure. The crude product was purified by silica gel columnchromatography (100-200 mesh; using 10% ethyl acetate in hexane) toobtain 1-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethanol as white solid(0.35 g, 9% yield). 1H NMR (400 MHz, CDCl₃): δ 8.14 (dd, 1H), 7.20 (dd,1H), 5.06 (q, 1H), 1.66 (d, 3H).

Step 3: 1-(5-(4-Fluorophenyl)-1,2,4-oxadiazol-3-yl)ethanone

To a stirred solution of1-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethanol (0.34 g, 1.92 mmol)in DCM (40 mL) was added Dess-Martin periodinane (2.7 g, 6.5 mmol) atroom temperature and the mixture stirred for 3 h. The reaction mixturewas filtered and washed with DCM (15 mL). To the filtrate was addedNaHCO₃ solution (10 mL) and DCM (30 mL). The organic layer wasseparated, washed with water (20 mL) followed by brine solution (20 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure to get crude compound. The crude compound was purified bysilica gel column chromatography (100-200 mesh; using 10% methanol inDCM) to obtain 1-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethanone asoff-white solid (0.25 g, 72% yield). 1H NMR (400 MHz, CDCl₃): δ 2.76 (s,3H), 7.23 (t, 2H), 7.23 (dd, 2H), LC-MS m/z calculated for [M+H]⁺207.17, found 206.87.

Step 4:1-(5-(4-Fluorophenyl)-1,2,4-oxadiazol-3-yl)-1-(pyridin-4-yl)ethanol

To a stirred solution of 4-iodopyridine (0.29 g, 0.463 mmol) in THF (30mL) at −78° C. was added n-BuLi (2.4 mL, 3.9 mmol) and the mixture wasstirred for 10 min. 1-(5-(4-Fluorophenyl)-1,2,4-oxadiazol-3-yl)ethanone(0.5 g, 2.79 mmol) in THF (5 mL) was then added to reaction, which wasthen stirred at −78° C. for 2 h. The reaction was then quenched withsaturated ammonium chloride solution (10 mL) and diluted with ethylacetate (50 mL). The organic layer was separated, washed with ammoniumchloride solution (3×150 mL) followed by brine solution (2×20 mL), driedover sodium sulfate, filtered and concentrated under reduced pressure toobtain crude product. The crude product was purified by columnchromatography (100-200μ silica gel and 30% ethyl acetate in hexane) toobtain 3-(4-fluorophenyl)-5-(1-(pyridin-4-yl)ethyl)isoxazole asoff-white solid (0.06 g, 29% yield). 1H NMR (400 MHz, CDCl₃): δ 8.60 (d,2H), 8.11 (dd, 2H), 7.48 (d, 2H), 7.19 (t, 2H), 3.40 (s, 1H), 1.99 (s,3H); LC-MS m/z calculated for [M+H]⁺ 286.09, found 286.2.

Example 304-(5-(1-Hydroxy-1-(pyridin-4-yl)ethyl)thiazol-2-yl)-2-(trifluoro-methyl)benzonitrile(synthetic method of Scheme 8)

Step 1: 4-(Thiazol-2-yl)-2-(trifluoromethyl)benzonitrile

A solution of 4-bromo-2-(trifluoromethyl)benzonitrile (0.5 g, 2 mmol) inDMF (5 mL) was purged with argon and 2-(tributylstannyl)thiazole (1.12g/0.9 mL, 3 mmol) and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (0.14 g,0.2 mmol) added. The reaction mixture was purged with argon for 5 minand retained in microwave for 30 min at 100° C. The reaction mixture wasdiluted with ice cold water (10 mL) and extracted with ethyl acetate(200 mL). The organic solvent was dried over sodium sulfate, filteredand the solvent was evaporated under reduced pressure to obtain crudeproduct. The crude product was purified by silica gel chromatography(100-200 mesh; 8% ethyl acetate in hexane) to give4-(thiazol-2-yl)-2-(trifluoromethyl)benzonitrile (0.42 g, 84% yield) aspale yellow solid. 1H NMR (400 MHz, DMSO-d₆): δ 8.42-8.39 (m, 2H), 8.27(d, 1H), 8.08 (d, 1H), 8.03 (d, 1H). LC-MS m/z calculated for [M+H]⁺255.01, found 255.0.

Step 2:4-(5-(1-Hydroxy-1-(pyridin-4-yl)ethyl)thiazol-2-yl)-2-(trifluoromethyl)-benzonitrile

A solution of diisopropylamine (0.08 mL, 0.59 mmol) in THF (7 mL) wascooled to −78° C., and 1.6M n-BuLi in hexanes (0.49 mL, 0.78 mmol)added. The reaction mixture was allowed to stir at 0° C. for 30 min,again cooled to −78° C. and a solution of4-(thiazol-2-yl)-2-(trifluoromethyl)benzonitrile (0.1 g, 0.39 mmol) inTHF (2 mL) added dropwise at −78° C. for 30 min. 4-Acetyl pyridine(0.048 mL, 0.43 mmol) in THF (2 mL) at −78° C. was then slowly added,the reaction was stirred for 1 hour and quenched with saturated ammoniumchloride (2 mL), and water (10 mL). The reaction mixture was extractedwith ethyl acetate (20 mL), the organic layer was dried over sodiumsulfate, filtered and the solvent was evaporated under reduced pressureto obtain crude product. The crude product was product purified by PrepTLC (5% methanol in dichloromethane) to give4-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)thiazol-2-yl)-2-(trifluoromethyl)benzonitrile(30 mg, 21%) as pale yellow solid in 99.1% HPLC purity. 1H NMR (400 MHz,DMSO-d₆): δ 8.54 (d, 2H), 8.36-8.32 (m, 2H), 8.24 (d, 1H), 8.03 (s, 1H),7.52-7.51 (m, 2H), 6.81 (s, 1H), 1.97 (s, 3H). LC-MS m/z calculated for[M+H]⁺ 376.07, found 375.7.

Example 311-(5-(4-Fluorophenyl)-1,3,4-oxadiazol-2-yl)-1-(pyridin-4-yl)ethanol(synthetic method of Schemes 11 and 3)

Step 1: 4-fluorobenzohydrazide

To a stirred solution of 4-fluoroethylbenzoate (4.5 g, 26.7 mmol) inEtOH (30 mL) was added NH₂NH₂.H₂O (6.67 g, 133.5 mmol) at roomtemperature and the solution refluxed at 85° C. for 10 h. The reactionwas cooled to room temperature, concentrated under reduced pressure, andthe solid washed with n-hexane (50 mL) and then dried to obtain4-fluorobenzohydrazide as a solid (4.2 g, quantitative yield). 1H NMR(400 MHz, DMSO-d₆): δ 9.85 (s, 1H), 7.86 (dd, 2H), 7.25 (t, 3H), 4.46(s, 1H), 3.47 (br s, 1H).

Step 2: 2-(4-Fluorophenyl)-1,3,4-oxadiazole

A stirred solution of 4-fluorobenzohydrazide (4.2 g, 27.2 mmol) intriethylorthoformate (27 mL) was heated at 140° C. for 5 h. The reactionwas evaporated under reduced pressure. The crude was purified by silicagel column chromatography (100-200 mesh; using 12% ethyl acetate inhexane) to afford 2-(4-fluorophenyl)-1,3,4-oxadiazole [Polshettiwar,Tetrahedron Letters, 49:879-883 (2008)] as off-white solid (2.5 g, 57%yield). 1H NMR (400 MHz, DMSO-d₆): δ 8.46 (s, 1H), 8.08 (dd, 2H), 7.19(dd, 2H); LC-MS m/z calculated for [M+H]⁺ 165.04, found 165.00.

Step 3:1-(5-(4-Fluorophenyl)-1,3,4-oxadiazol-2-yl)-1-(pyridin-4-yl)ethanol

To a stirred solution of 2-(4-fluorophenyl)-1,3,4-oxadiazole (0.8 g, 2.4mmol) in THF (10 mL) was added LDA (2.9 mmol) at −78° C. (0.308 g, 2.9mmol) and mixture was stirred for 20 min. A solution of 4-acetylpyridine (0.377 g, 3.1 mmol) in THF (10 mL) was added at −78° C. andstirred for 2 h. The reaction mixture was quenched with saturated NH₄Clsolution (50 mL), extracted with ethyl acetate (3×60 mL), washed withbrine solution (60 mL), dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by silica gelcolumn chromatography (100-200 mesh; using 90% ethyl acetate in hexanes)to obtain1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-1-(pyridin-4-yl)ethanol asoff-white solid (combined yield for 2 batches: 0.051 g, 4% yield). 1HNMR (400 MHz, DMSO-d₆): δ 8.58 (s, 2H), 7.99 (t, 2H), 7.48 (d, 2H), 7.04(d, 2H), 6.98 (s, 1H), 1.94 (s, 3H); LC-MS m/z calculated for [M+H]⁺286.09, found 286.08.

Example 32 3-(4-Fluorophenyl)-5-(1-(pyridin-4-yl)ethyl)isoxazole(synthetic method of Schemes 12 and 1)

Step 1: 4-Fluorobenzaldehyde oxime

To a solution of 4-fluorobenzaldehyde (3.0 g, 24.1 mmol) in MeOH (15 mL)was added NH₂OH.HCl (2.0 g, 29.1 mmol) and Na₂CO₃ (1.53 g, 14.4 mmol)and the reaction stirred for 4 hours at room temperature. The reactionwas concentrated under reduced pressure, extracted with DCM (2×100 mL),and the organic layer washed with water (2×50 mL) followed by brinesolution (2×25 mL). The organic layer was concentrated under reducedpressure to obtain 4-fluorobenzaldehyde oxime [Brain, J. Am. Chem. Soc.,133:949-957 (2011)] as white solid (2 g, 61% yield). 1H NMR (400 MHz,CDCl₃): δ 8.12 (s, 1H), 7.55 (dd, 2H), 7.06 (t, 2H).

Step 2: 1-(3-(4-Fluorophenyl)isoxazol-5-yl)ethanol

To a stirred solution of 4-fluorobenzaldehyde oxime (0.2 g, 1.4 mmol) inDCM (10 mL) was added N-chlorosuccinamide (0.1 g, 1.4 mmol) and thereaction stirred for 1 hour at room temperature. But-3-yn-2-ol (0.23 g,1.68 mmol) was added and the reaction mixture stirred at reflux for 3 h.After completion of the reaction (as monitored by TLC), the mixture wasextracted with DCM (3×100 mL), the organic layer washed with water (100mL) followed by brine (100 mL), dried over sodium sulfate, andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography (60-120 mesh; using 50% ethyl acetatein hexanes) to obtain 1-(3-(4-fluorophenyl)isoxazol-5-yl)ethanol asliquid (0.15 g, 50% yield). 1H NMR (400 MHz, CDCl₃): δ 7.76 (dd, 2H),7.05 (t, 2H), 6.48 (s, 1H), 5.04 (q, 1H), 1.63 (d, 3H).

Step 3: 1-(3-(4-Fluorophenyl)isoxazol-5-yl)ethanone

To a stirred solution of 1-(3-(4-fluorophenyl)isoxazol-5-yl)ethanol(0.15 g, 0.724 mmol) in DCM (10 mL) was added Dess-Martin periodinane(0.46 g, 1.08 mmol) at room temperature. The resulting solution wasstirred for 16 h. The reaction mixture was filtered and washed with DCM(3×50 mL). The organic layer was washed with water (50 mL) followed bybrine solution (50 mL), dried over sodium sulfate and concentrated underreduced pressure to obtain crude product. The crude product was purifiedby silica gel column chromatography (100-200 mesh; using 80% ethylacetate in hexane) to obtain 1-(3-(4-fluorophenyl)isoxazol-5-yl)ethanoneas off-white solid (0.1 g, 68% yield). 1H NMR (400 MHz, CDCl₃): δ 7.81(t, 2H), 7.20 (s, 1H), 7.17 (d, 2H), 2.66 (s, 3H).

Step 4: 3-(4-Fluorophenyl)-5-(1-(pyridin-4-yl)ethyl)isoxazole

To a stirred solution of 4-iodopyridine (0.3 g, 1.463 mmol) in THF (10mL) was added n-BuLi (0.6 mL, 0.96 mmol) at −78° C. and stirred for 10min. A solution of 1-(3-(4-fluorophenyl)isoxazol-5-yl)ethanone (0.1 g,0.484 mmol) in THF (5 mL) was added to the reaction and the mixturestirred at −78° C. for 2 h. The reaction was quenched with saturatedammonium chloride solution (10 mL) and diluted with ethyl acetate (50mL). The organic layer was separated, washed with saturated ammoniumchloride (3×150 mL) followed by brine solution (2×20 mL). The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure to obtain crude product. The crude product was purifiedby column chromatography (100-200μ silica gel; 50% ethyl acetate inhexane) to obtain 3-(4-fluorophenyl)-5-(1-(pyridin-4-yl)ethyl)isoxazoleas off-white solid (0.04 g, 29% yield). 1H NMR (400 MHz, DMSO-d₆): δ8.55 (d, 2H), 7.91 (dd, 2H), 7.46 (d, 2H), 7.32 (t, 2H), 6.81 (s, 1H),7.04 (s, 1H), 1.86 (s, 3H); LC-MS m/z calculated for [M+H]⁺ 285.10,found 285.1.

Example 33 (2-(4-Fluorophenyl)thiazol-5-yl)(pyridin-4-yl)methanone(synthetic method of Schemes 1 and 2A)

Step 1: (2-(4-Fluorophenyl)thiazol-5-yl)(pyridin-4-yl)methanone

To a stirred solution of(2-(4-fluorophenyl)thiazol-5-yl)(pyridin-4-yl)methanol (0.55 g, 1.92mol) in DCM (20 mL) was added Dess-Martin periodinane (1.6 g, 3.84 mol)at room temperature. The resulting solution was stirred for 1 h. To thereaction mixture was added NaHCO₃ solution (20 mL) and ethyl acetate (50mL). The organic layer was extracted with ethyl acetate (2×20 mL),washed with brine solution (2×20 mL), dried over anhydrous sodiumsulfate and the solvent removed via distillation under reduced pressure.The crude was purified through silica gel (100-200 mesh) columnchromatography using 10% methanol in DCM) to obtain(2-(4-fluorophenyl)thiazol-5-yl)(pyridin-4-yl)methanone as off-whitesolid (0.4 g, 67% yield). 1H NMR (400 MHz, DMSO-d₆): δ 8.86 (d, 2H),8.51 (s, 1H), 8.19 (dd, 2H), 7.82 (d, 2H), 7.45 (t, 2H); LC-MS m/zcalculated for [M+H]⁺ 285.04 found 284.98.

Step 2:1-(2-(4-Fluorophenyl)thiazol-5-yl)-2-methyl-1-(pyridin-4-yl)propan-1-ol

To a stirred solution of(2-(4-fluorophenyl)thiazol-5-yl)(pyridin-4-yl)methanone (0.1 g, 0.352mmol) in THF (10 mL) was added isopropyl magnesium bromide (0.1 g, 0.704mmol) at 0° C. The reaction mixture was stirred for 1 hour at roomtemperature. After completion of the reaction, the reaction mixture wasquenched with ammonium chloride (5 mL) at 0° C., extracted with ethylacetate (2×20 mL), washed with water followed by brine (20 mL), driedover Na₂SO₄, and concentrated under reduced pressure. The crude waspurifying by the preparative TLC (Mobile phase: 10% MeOH in DCM) toobtain pure1-(2-(4-fluorophenyl)thiazol-5-yl)-2-methyl-1-(pyridin-4-yl)propan-1-ol(0.023 g, 20% yield). 1H NMR (400 MHz, DMSO-d₆): δ 8.52 (d, 2H), 7.92(t, 3H), 7.56 (d, 2H), 7.27 (t, 2H), 6.22 (s, 1H), 2.79 (t, 1H), 0.98(d, 3H), 0.71 (d, 3H); LC-MS m/z calculated for [M+H]⁺ 329.10, found329.1.

Example 341-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)-1-(pyridin-4-yl)ethanol(synthetic method of Schemes 10B & 1)

Step 1: Ethyl 2-hydroxy-2-(pyridin-4-yl)propanoate

4-Iodopyridine (15.0 g, 73 mmol) was taken up in dry THF (600 mL) andcooled to 0° C. and then ethylmagnesium bromide (3M solution in THF,41.8 mL) was gradually added, maintaining the temperature at 0° C. overthe period of 30 mins. To the above reaction mixture was then added asolution of ethyl 2-oxopropanoate (12.13 g, 104 mmol) in THF (100 mL).The reaction mixture was stirred at 0° C. for 1 hr. The reactionprogress was monitored by TLC using solvent system MeOH:DCM (5:95).After completion of reaction, the reaction mixture was quenched withice-cold water and extracted with EtOAc (3×1 Lit). The combined organiclayers were dried over Na₂SO₄, and concentrated under vacuum. The crudeproduct residue was combined with a batch of crude product obtained froma second reaction carried out at the same scale, and was purified bycolumn chromatography using silica (100-200 mesh) and solvent systemEtOAc:hexane (4:6) to obtain 7 g (25%) of ethyl2-hydroxy-2-(pyridin-4-yl)propanoate as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 8.52 (d, 2H, J=6 Hz), 7.44 (d, 2H, J=6. Hz), 6.2 (s, 1H),4.08 (q, 2H, J=7.2 Hz), 1.60 (s, 1H), 1.12 (t, 3H, J=7.2 Hz); LC-MS m/zcalculated for [M+H]⁺ 196.09, found 196.2.

Step 2: 4-Fluoro-N′-hydroxybenzimidamide

To a stirred solution of 4-fluorobenzonitrile (10 g, 82.5 mmol) in EtOH(71 mL) was added NH₂OH.HCl (6.42 g, 92.1 mmol), followed by NaOHpellets (3.69 g, 92.1 mmol). The resulting reaction mixture was thenheated at reflux for 3 h. The reaction progress was monitored by TLCusing solvent system EtOAc:hexane (1:1). After completion of reactionthe solvent was evaporated under reduced pressure and the minimum amountof water (ca. 30 mL) was added to the residue. The mixture was extractedwith dichloromethane (3×300 mL), dried over Na₂SO₄, and concentratedunder vacuum. The crude compound obtained was recrystallized from hottoluene to obtain 8.0 g (63%) of 4-fluoro-N-hydroxybenzimidamide as acolorless solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.6 (s, 1H), 7.07-7.67 (m,2H), 7.18 (t, 2H, J=8.8 Hz), 5.80 (br s, 2H); LC-MS m/z calculated for[M+H]⁺ 155.05, found 155.1.

Step 3:1-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)-1-(pyridin-4-yl)ethanol

Sodium hydride (60%, 6.00 g, 150 mmol) was taken up in THF (250 mL)under nitrogen atmosphere, and then a solution of4-fluoro-N′-hydroxybenzimidamide (Step 2; 23.22 g, 150 mmol) in THF (250mL) was added. The resulting reaction mixture was heated at 50° C. for15 min, and then a solution of ethyl2-hydroxy-2-(pyridin-4-yl)propanoate (Step 1; 25 g, 120 mmol) in THF(250 mL) was added. The mixture was stirred for 1 hr at 50° C. Theprogress of reaction was monitored by TLC using solvent systemEtOAc:hexane (7:3). After completion of reaction, the solvent wasconcentrated to one third of the total volume. The crude mixture waspoured into ice water and extracted with EtOAc (3×500 mL). The combinedorganic extract was dried over Na₂SO₄ and concentrated under vacuum. Thecrude residue was washed with water several times to obtain a solidwhich was then washed with hexane (100 mL) followed by 50 mL of chilledether to obtain 14 g (38%) of1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-1-(pyridin-4-yl)ethanol as acolorless solid. HPLC purity: 99.4%; ¹H NMR (400 MHz, DMSO-d₆): δ 8.58(d, 2H, J=5.6 Hz), 8.06-8.03 (m, 2H), 7.51 (d, 2H, J=6.4 Hz), 7.39 (t,2H, J=8.8 Hz), 7.09 (s, 1H), 1.96 (s, 3H); LC-MS m/z calculated for[M+H]⁺ 286.09, found 286.1.

Examples 35 & 36 Enantiomer #1 and Enantiomer #21-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)-1-(pyridin-4-yl)ethanol

Racemic1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-1-(pyridin-4-yl)ethanol(Example 34) (20 g) was dissolved in mobile phase (90:10)n-heptane:ethanol containing 0.1% DEA and subjected to chiral HPLCpurification (30 mg in 5 mL per injection) using Chiralpak IA column(250 mm×20 mm×5 nm), mobile phase (90:10) n-heptane:ethanol containing0.1% DEA, flow rate 18.0 mL/min. Eluted fractions of the two enantiomerswere separately collected and each of these fractions was concentratedto afford 7.55 g (76% recovery) of(−)-1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-1-(pyridin-4-yl)ethanol(Example 35) (Enantiomer #1, 99.78% ee, [α]_(D) ^(23.6) −77.4 (c 1.0,MeOH)), and 8.10 g (81% recovery) of(+)-1-(3-(4-fluoro-phenyl)-1,2,4-oxadiazol-5-yl)-1-(pyridin-4-yl)ethanol(Example 36) (Enantiomer #2, 97.07% ee, [α]_(D) ^(23.3) +77.26 (c 1.0,MeOH)).

Examples 54 & 55 Enantiomer #1 and Enantiomer #2 of1-(5-(4-Fluorophenyl)thiazol-2-yl)-1-(pyridin-4-yl)ethanol

Racemic 1-(5-(4-fluorophenyl)thiazol-2-yl)-1-(pyridin-4-yl)ethanol(Example 14) (3.5 g), was dissolved in mobile phase (100% ethanolcontaining 0.1% DEA) and subjected to chiral HPLC purification (50 mg in5 mL per injection) using ChiralpakIA® IA [250 mm×4.6 mm×5 μm] column,mobile phase 100% ethanol containing 0.1% DEA; flow rate 9.0 mL/min.Eluted fractions of the two enantiomers were separately collected andeach of these fractions was concentrated to afford 1.6 g (91% recovery)of (−)-1-(5-(4-fluorophenyl)thiazol-2-yl)-1-(pyridin-4-yl)ethanol(Example 54) (Enantiomer #1, 99.8% ee, [α]_(D) ^(25.2) −107.30 (c 1.0,DMF)), and 1.5 g (86% recovery) of(+)-1-(5-(4-fluorophenyl)thiazol-2-yl)-1-(pyridin-4-yl)ethanol (Example55) (Enantiomer #2, 99.0% ee). Enantiomer #2 (1.5 g) was again purifiedby similar method to obtain 1.0 g (overall 57% recovery) with chiralpurity of 99.9% ee, [α]_(D) ^(24.2) +107.82 (c 1.0, DMF).

Example 65 1-(2-(4-Fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethylacetate (synthetic method of Scheme 19)

To a stirred solution of1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol (Example 7)(5.0 g, 16.6 mmol) in THF (200 mL) was added KOtBu (4.65 g, 41.5 mmol)at room temperature. The mixture was stirred for 15 mins, and then itwas cooled to 0° C. Acetyl chloride (4.73 mL, 66.6 mmol) was addeddropwise to the reaction mixture and stirring was continued at 0° C. for20 min. Water (250 mL) was added to the reaction mixture, which was thenextracted with EtOAc (4×1 L). The combined organic layers were washedwith cold water (3×150 mL) and brine (250 mL), and then concentratedunder vacuum. The crude product residue obtained was purified by columnchromatography using silica (100-200 mesh) and ethyl acetate/hexane(4:6) as eluent to afford 3.75 g (66%) of1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethyl acetate as alight brown solid. 1H NMR (400 MHz, CDCl₃): δ 8.62 (d, 1H, J=4.8 Hz),7.87 (m, 2H), 7.62 (s, 1H), 7.29 (d, 2H, J=4.8 Hz), 7.10 (t, 1H, J=8.1Hz), 2.28 (s, 3H), 2.15 (s, 3H); LC-MS m/z calculated for [M+H]⁺ 343.08,found 343.1.

Example 68 1-(2-(4-Fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanamine(synthetic method of Scheme 18)

A stirred solution ofN-(1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethyl)acetamide(Example 69) (0.04 g, 0.12 mmol) in concentrated HCl (0.07 mL, 3.03mmol) was heated at 100° C. for 24 hrs in a sealed glass tube. Thereaction mixture was then cooled to room temperature and neutralizedwith 10% NaOH solution (2 mL). The aqueous layer was extracted withethyl acetate (3×100 mL), and the combined organic layers wereconcentrated under vacuum. The crude product residue obtained waspurified by preparative TLC using eluting solvent as MeOH:CH₂Cl₂ (3:7)to afford 20 mg (38%) of1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanamine as acolorless solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.50 (d, 2H, J=5.6 Hz),7.91-7.88 (m, 2H), 7.70 (s, 1H), 7.51 (d, 2H, J=6.4 Hz), 7.28 (t, 2H,J=8.8 Hz), 2.81 (s, 2H); 1.85 (s, 3H); LC-MS m/z calculated for [M+H]⁺300.09, found 300.1.

Example 69N-(1-(2-(4-Fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethyl)acetamide(synthetic method of Scheme 18)

A stirred solution of1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol (Example 7)(0.450 g, 1.50 mmol) in MeCN (2.25 mL) was heated at 90° C. and thenconc. H₂SO₄ (0.58 mL) in MeCN (2.25 mL) was added. The reaction mixturewas stirred at 90° C. for 3 hrs, then it was cooled to room temperatureand ice was added. The resulting mixture was neutralized with 10% NaOHsolution, extracted with ethyl acetate (3×250 mL), and the combinedorganic layers were concentrated under vacuum. The crude productobtained was purified by column chromatography using silica gel (100-200mesh) and MeOH:CH₂Cl₂ (3:7) as eluent to afford 95 mg (19%) ofN-(1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethyl)acetamide asa colorless solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.72 (br s, 1H), 8.48(dd, 2H, J=4.4, 1.6 Hz), 7.93 (m, 2H), 7.80 (s, 1H), 7.29 (t, 2H, J=8.8Hz), 7.20 (dd, 2H, J=4.4, 1.6 Hz); 1.97 (s, 3H), 1.90 (s, 3H), LC-MS m/zcalculated for [M+H]⁺ 342.10, found 342.1.

The following tables, i.e., Tables 1 and 2, provide a summary of thesynthetic methods utilized to prepare the Compounds of the Inventionidentified therein. Table 1 provides the synthetic methods used withreference to the Schemes described above, and Table 2 provides thespectroscopic data obtained and utilized in the characterization of theprepared compounds.

TABLE 1 Synthesis method Ex. Structure Name (Scheme #) 1

1-(5-(4-methoxyphenyl)-pyridin- 2-yl)-1-(pyridin-4-yl)-ethanol 1 2

1-(5-(4-methoxyphenyl)-pyridin- 2-yl)-1-(pyridin-4-yl)-ethanol,enantiomer #1 1 3

1-(5-(4-methoxyphenyl)-pyridin- 2-yl)-1-(pyridin-4-yl)-ethanol,enantiomer #2 1 4

1-(2-(4-fluorophenyl)-thiazol-5- yl)-1-(pyridin-4-yl)propan-1-ol 1, 2 5

1-(5-(4-fluorophenyl)-pyridin-2- yl)-1-(pyridin-4-yl)ethanol 1 6

1-(5-(3-fluoro-4- methoxyphenyl)-pyridin-2-yl)- 1-(pyridin-4-yl)ethanol1 7

1-(2-(4-fluorophenyl)-thiazol-5- yl)-1-(pyridin-4-yl)ethanol 1, 2, 3 8

(+)-1-(2-(4-fluorophenyl)- thiazol-5-yl)-1-(pyridin-4- yl)ethanol(enantiomer #1) 3 9

(−)-1-(2-(4-fluorophenyl)- thiazol-5-yl)-1-(pyridin-4- yl)ethanol(enantiomer #2) 3 10

4-(6-(1-hydroxy-1-(pyridin-4- yl)-ethyl)pyridin-3-yl)- benzonitrile 1 11

1-(5-(4-fluorophenyl)pyrazin-2- yl)-1-(pyridin-4-yl)ethanol 4 12

6′-(1-hydroxy-1-pyridin-4- ylethyl)-3,3′-bipyridine-6- carbonitrile 1 13

1-[5-(4-fluorophenyl)-1,3- thiazol-2-yl]-1-pyridin-4- ylpropan-1-ol 7 14

1-[5-(4-fluorophenyl)-1,3- thiazol-2-yl]-1-pyridin-4- ylethanol 3 15

5-[5-(1-hydroxy-1-pyridin-4- ylethyl)thien-2-yl]-1-methylpyridin-2(1H)-one 6 16

(+)-5-[5-(1-Hydroxy-1-pyridin- 4-yl-ethyl)-thiophen-2-yl]-1-methyl-1H-pyridin-2-one (enantiomer #1) 6 17

(−)-5-[5-(1-Hydroxy-1-pyridin- 4-yl-ethyl)-thiophen-2-yl]-1-methyl-1H-pyridin-2-one (enantiomer #2) 6 18

1-[2-(1H-pyrazol-4-yl)-1,3- thiazol-5-yl]-1-pyridin-4- ylpropan-1-ol 1,2, 3 19

(−)-1-[2-(1H-pyrazol-4-yl)-1,3- thiazol-5-yl]-1-pyridin-4-ylpropan-1-ol, (enantiomer #1) 3 20

(+)-1-[2-(1H-pyrazol-4-yl)-1,3- thiazol-5-yl]-1-pyridin-4-ylpropan-1-ol, (enantiomer #2) 3 21

1-[5-(4-fluorophenyl)-1,3,4- thiadiazol-2-yl]-1-pyridin-4- ylpropan-1-ol9, 2, 1 22

1-[2-(6-fluoropyridin-3-yl)-1,3- thiazol-5-yl]-1-pyridin-4- ylethanol 623

1-[2-(4-fluorophenyl)-1,3- oxazol-5-yl]-1-pyridin-4- ylethanol 7 24

[2-(4-fluorophenyl)-1,3-thiazol- 5-yl](pyridin-4-yl)methanol 3 25

5-[2-(4-Fluoro-phenyl)-thiazol- 5-yl]-5,6,7,8-tetrahydro-isoquinolin-5-ol 3 26

1-Pyridin-4-yl-1-[2-(4- trifluoromethyl-phenyl)-thiazol- 5-yl]-ethanol 327

1-[2-(2,4-Difluoro-phenyl)- thiazol-5-yl]-1-pyridin-4-yl- ethanol 3 28

1-[2-(4-Chloro-phenyl)-thiazol- 5-yl]-1-pyridin-4-yl-ethanol 3 29

1-[5-(4-Fluoro-phenyl)- [1,2,4]oxadiazol-3-yl]-1- pyridin-4-yl-ethanol10A, 1 30

4-[5-(1-Hydroxy-1-pyridin-4- yl-ethyl)-thiazol-2-yl]-2-trifluoromethyl-benzonitrile 8A, 3 31

1-[5-(4-Fluoro-phenyl)- [1,3,4]oxadiazol-2-yl]-1-pyridin- 4-yl-ethanol11, 3 32

1-[3-(4-Fluoro-phenyl)-isoxazol- 5-yl]-1-pyridin-4-yl-ethanol 12, 1 33

1-[2-(4-Fluoro-phenyl)-thiazol- 5-yl]-2-methyl-1-pyridin-4-yl-propan-1-ol 1, 2A 34

1-(3-(4-Fluorophenyl)-1,2,4- oxadiazol-5-yl)-1-(pyridin-4- yl)ethanol10B, 1 35

(−)-1-(3-(4-Fluorophenyl)-1,2,4- oxadiazol-5-yl)-1-(pyridin-4-yl)ethanol (enantiomer #1) 10B, 1 36

(+)-1-(3-(4-Fluorophenyl)-1,2,4- oxadiazol-5-yl)-1-(pyridin-4-yl)ethanol (enantiomer #2) 10B, 1 37

1-(5-(4-fluorophenyl)furan-2- yl)-1-(pyridin-4-yl)ethanol 8B, 3 38

2-chloro-4-(5-(1-hydroxy-1- (pyridin-4-yl)ethyl)thiazol-2-yl)benzonitrile 3 39

1-(2-(4-chloro-3- (trifluoromethyl)phenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol 3 40

2-fluoro-5-(5-(1-hydroxy-1- (pyridin-4-yl)ethyl)thiazol-2-yl)benzonitrile 8A, 3 41

1-(2-(3-chloro-4- (trifluoromethyl)phenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol 8A, 3 42

2-chloro-5-(5-(1-hydroxy-1- (pyridin-4-yl)ethyl)thiazol-2-yl)benzonitrile 3 43

1-(2-(3,4-dichlorophenyl)thiazol- 5-yl)-1-(pyridin-4-yl)ethanol 3 44

1-(2-(3,4-difluorophenyl)thiazol- 5-yl)-1-(pyridin-4-yl)ethanol 3 45

1-(2-(4-(methylsulfonyl)- phenyl)thiazol-5-yl)-1-(pyridin- 4-yl)ethanol3 46

1-(2-(3-chloro-4- fluorophenyl)thiazol-5-yl)-1- (pyridin-4-yl)ethanol 347

1-(2-(4-fluorophenyl)thiazol- 5-yl)-3-methyl-1-(pyridin-4- yl)butan-1-ol3, 2A 48

1-(3-(4-fluorophenyl)isothiazol- 5-yl)-1-(pyridin-4-yl)ethanol 13, 3 49

1-(3-(4-fluorophenyl)-1H- pyrazol-5-yl)-1-(pyridin-4- yl)ethanol 14, 2A50

1-(5-(4-fluorophenyl)isoxazol- 3-yl)-1-(pyridin-4-yl)ethanol 15, 2A 51

1-(2-phenylthiazol-5-yl)-1- (pyridin-4-yl)ethanol 3 52

1-(3-(4-fluorophenyl)-1,2,4- thiadiazol-5-yl)-1-(pyridin-4- yl)ethanol16, 1 53

1-(5-(4-fluorophenyl)-1,2,4- thiadiazol-3-yl)-1-(pyridin-4- yl)ethanol4, 17, 1 54

(−)-1-(5-(4-fluorophenyl)thiazol- 2-yl)-1-(pyridin-4-yl)ethanol(enantiomer #1) 3 55

(+)-1-(5-(4-fluorophenyl)thiazol- 2-yl)-1-(pyridin-4-yl)ethanol(enantiomer #2) 3 56

4-(5-(1-hydroxy-1-(pyridin-4- yl)ethyl)thiazol-2-yl)benzonitrile 3 57

1-(5-(1H-pyrazol-4-yl)oxazol-2- yl)-1-(pyridin-4-yl)propan-1-ol 3 58

5-(5-(1-hydroxy-1-(pyridin-4- yl)ethyl)furan-2-yl)-1-methylpyridin-2(1H)-one 6 59

5-(2-(4-fluorophenyl)thiazol-5- yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol 3 60

5-(5-(1-hydroxy-1-(pyridin-4- yl)-ethyl)oxazol-2-yl)-1-methylpyridin-2(1H)-one 8C, 3 61

1-(5-(4-fluorophenyl)-1,3,4- thiadiazol-2-yl)-1-(pyridin-4- yl)ethanol9, 2, 1 62

1-(6′-(1-hydroxy-1-(pyridin-4- yl)ethyl)-[3,3′-bipyridin]-6-yl)pentan-1-one 1 63

1-(5-(4-fluorophenyl)isothiazol- 3-yl)-1-(pyridin-4-yl)ethanol 7, 17, 164

1-(pyridin-4-yl)-1-(2-(pyrimidin- 5-yl)thiazol-5-yl)ethanol 3 65

1-(2-(4-fluorophenyl)thiazol-5- yl)-1-(pyridin-4-yl)ethyl acetate 19 66

1-(2-(4-fluorophenyl)thiazol-5- yl)-1-(pyridin-4-yl)ethyl propionate 1967

1-(2-(4-fluorophenyl)thiazol-5- yl)-1-(pyridin-4-yl)ethyl butyrate 19 68

1-(2-(4-fluorophenyl)thiazol-5- yl)-1-(pyridin-4-yl)ethanamine 18 69

N-(1-(2-(4-fluorophenyl)thiazol- 5-yl)-1-(pyridin-4- yl)ethyl)acetamide18

All compounds that have a chiral center are racemic mixtures, except asindicated.

TABLE 2 LC-MS LC-MS Exact [M + H] retention Ex. Structure Name mass⁺(m/z) time (min) 1

1-(5-(4- methoxyphenyl)- pyridin-2-yl)-1- (pyridin-4-yl)- ethanol 306.14307.3 1.17 2

1-(5-(4- methoxyphenyl)- pyridin-2-yl)-1- (pyridin-4-yl)- ethanol,enantiomer #1 306.14 307.1 1.15 3

1-(5-(4- methoxyphenyl)- pyridin-2-yl)-1- (pyridin-4-yl)- ethanol,enantiomer #2 306.14 307.1 1.15 4

1-(2-(4- fluorophenyl)- thiazol-5-yl)-1- (pyridin-4- yl)propan-1-ol314.09 315.1 1.60 5

1-(5-(4- fluorophenyl)- pyridin-2-yl)-1- (pyridin-4-yl)ethanol 294.12295.5 1.49 6

1-(5-(3-fluoro-4- methoxyphenyl)- pyridin-2-yl)-1- (pyridin-4-yl)ethanol324.13 325.5 1.46 7

1-(2-(4- fluorophenyl)- thiazol-5-yl)-1- (pyridin-4-yl)ethanol 300.07301.6 1.01 8

(+)-1-(2-(4- fluorophenyl)- thiazol-5-yl)-1- (pyridin-4-yl)ethanol(enantiomer #1) 300.07 301.5 1.08 9

(−)-1-(2-(4- fluorophenyl)- thiazol-5-yl)-1- (pyridin-4-yl)ethanol(enantiomer #2) 300.07 301.5 1.09 10

4-(6-(1-hydroxy-1- (pyridin-4-yl)- ethyl)pyridin-3-yl)- benzonitrile301.12 302.2 0.46 11

1-(5-(4- fluorophenyl)pyrazin- 2-yl)-1-(pyridin-4- yl)ethanol 295.11296.1 0.82 12

6′-(1-hydroxy-1- pyridin-4-ylethyl)- 3,3′-bipyridine-6- carbonitrile302.12 303.1 1.50 13

1-[5-(4- fluorophenyl)-1,3- thiazol-2-yl]-1- pyridin-4-ylpropan- 1-ol314.09 315.1 1.01 14

1-[5-(4- fluorophenyl)-1,3- thiazol-2-yl]-1- pyridin-4-ylethanol 300.07301.4 0.92 15

5-[5-(1-hydroxy-1- pyridin-4- ylethyl)thien-2-yl]- 1-methylpyridin-2(1H)-one 312.09 313.1 0.40 16

(+)-5-[5-(1- Hydroxy-1-pyridin- 4-yl-ethyl)-thiophen- 2-yl]-1-methyl-1H-pyridin-2-one (enantiomer #1) 312.09 313.6 0.95 17

(−)-5-[5-(1-Hydroxy- 1-pyridin-4-yl- ethyl)-thiophen-2- yl]-1-methyl-1H-pyridin-2-one (enantiomer #2) 312.09 313.6 0.95 18

1-[2-(1H-pyrazol-4- yl)-1,3-thiazol-5-yl]- 1-pyridin-4- ylpropan-1-ol286.09 287.1 0.51 19

(−)-1-[2-(1H- pyrazol-4-yl)-1,3- thiazol-5-yl]-1- pyridin-4-ylpropan-1-ol (enantiomer #1) 286.09 287.1 0.78 20

(+)-1-[2-(1H- pyrazol-4-yl)-1,3- thiazol-5-yl]-1- pyridin-4-ylpropan-1-ol (enantiomer #2) 286.09 287.1 0.85 21

1-[5-(4- fluorophenyl)-1,3,4- thiadiazol-2-yl]-1- pyridin-4-ylpropan-1-ol 315.08 316.1 1.29 22

1-[2-(6- fluoropyridin-3-yl)- 1,3-thiazol-5-yl]-1- pyridin-4-ylethanol301.07 302.1 1.10 23

1-[2-(4- fluorophenyl)-1,3- oxazol-5-yl]-1- pyridin-4-ylethanol 284.10285.1 1.15 24

[2-(4-fluorophenyl)- 1,3-thiazol-5- yl](pyridin-4- yl)methanol 286.06287.0 4.97 25

5-[2-(4-Fluoro- phenyl)-thiazol-5- yl]-5,6,7,8- tetrahydro-isoquinolin-5-ol 326.09 327.1 5.49 26

1-Pyridin-4-yl-1-[2- (4-trifluoromethyl- phenyl)-thiazol-5- yl]-ethanol350.07 351.0 1.47 27

1-[2-(2,4-Difluoro- phenyl)-thiazol-5- yl]-1-pyridin-4-yl- ethanol318.06 319.0 1.32 28

1-[2-(4-Chloro- phenyl)-thiazol-5- yl]-1-pyridin-4-yl- ethanol 316.04317.4 1.40 29

1-[5-(4-Fluoro- phenyl)- [1,2,4]oxadiazol-3- yl]-1-pyridin-4-yl- ethanol285.09 286.2 4.92 30

4-[5-(1-Hydroxy-1- pyridin-4-yl-ethyl)- thiazol-2-yl]-2-trifluoromethyl- benzonitrile 375.07 375.7 1.32 31

1-[5-(4-Fluoro- phenyl)- [1,3,4]oxadiazol-2- yl]-1-pyridin-4-yl- ethanol285.09 286.1 4.45 32

1-[3-(4-Fluoro- phenyl)-isoxazol-5- yl]-1-pyridin-4-yl- ethanol 284.10285.1 5.11 33

1-[2-(4-Fluoro- phenyl)-thiazol-5- yl]-2-methyl-1- pyridin-4-yl-propan-1-ol 328.10 329.1 5.75 34

1-(3-(4- Fluorophenyl)-1,2,4- oxadiazol-5-yl)-1- (pyridin-4-yl)ethanol285.09 286.1 5.18 35

1-(3-(4- Fluorophenyl)-1,2,4- oxadiazol-5-yl)-1- (pyridin-4-yl)ethanol(enantiomer #1) 285.09 286.1 2.36 36

1-(3-(4- Fluorophenyl)-1,2,4- oxadiazol-5-yl)-1- (pyridin-4-yl)ethanol(enantiomer #2) 285.09 286.7 2.31 37

1-(5-(4- fluorophenyl)furan- 2-yl)-1-(pyridin-4- yl)ethanol 283.10 284.11.27 38

2-chloro-4-(5-(1- hydroxy-1-(pyridin- 4-yl)ethyl)thiazol-2-yl)benzonitrile 341.04 342.1 5.42 39

1-(2-(4-chloro-3- (trifluorometh- yl)phenyl)thiazol-5- yl)-1-(pyridin-4-yl)ethanol 384.03 385.1 1.62 40

2-fluoro-5-(5-(1- hydroxy-1-(pyridin- 4-yl)ethyl)thiazol-2-yl)benzonitrile 325.07 326.6 1.30 41

1-(2-(3-chloro-4- (trifluorometh- yl)phenyl)thiazol-5- yl)-1-(pyridin-4-yl)ethanol 384.03 385.6 1.60 42

2-chloro-5-(5-(1- hydroxy-1-(pyridin- 4-yl)ethyl)thiazol-2-yl)benzonitrile 341.04 342.5 1.15 43

1-(2-(3,4- dichlorophenyl)thi- azol-5-yl)-1-(pyridin- 4-yl)ethanol350.00 351.3 1.47 44

1-(2-(3,4- difluorophenyl)thi- azol-5-yl)-1-(pyridin- 4-yl)ethanol318.06 319.1 5.39 45

1-(2-(4- (methylsulfon- yl)phenyl)thiazol-5- yl)-1-(pyridin-4-yl)ethanol 360.06 361.1 1.36 46

1-(2-(3-chloro-4- fluorophenyl)thiazol- 5-yl)-1-(pyridin-4- yl)ethanol334.03 335.1 3.01 47

1-(2-(4- fluorophenyl)thiazol- 5-yl)-3-methyl-1- (pyridin-4-yl)butan-1-ol 342.12 343.1 6.08 48

1-(3-(4- fluorophenyl)iso- thiazol-5-yl)-1- (pyridin-4-yl)ethanol 300.07301.1 5.45 49

1-(3-(4- fluorophenyl)-1H- pyrazol-5-yl)-1- (pyridin-4-yl)ethanol 283.11285.1 4.64 50

1-(5-(4- fluorophenyl)isox- azol-3-yl)-1-(pyridin- 4-yl)ethanol 284.10285.1 5.21 51

1-(2-phenylthiazol- 5-yl)-1-(pyridin-4- yl)ethanol 282.08 283.1 5.02 52

1-(3-(4- fluorophenyl)-1,2,4- thiadiazol-5-yl)-1- (pyridin-4-yl)ethanol301.07 302.9 5.75 53

1-(5-(4- fluorophenyl)-1,2,4- thiadiazol-3-yl)-1- (pyridin-4-yl)ethanol301.07 302.1 5.24 54

1-(5-(4- fluorophenyl)thiazol- 2-yl)-1-(pyridin-4- yl)ethanol(enantiomer #1) 300.07 301.1 1.65 55

1-(5-(4- fluorophenyl)thiazol- 2-yl)-1-(pyridin-4- yl)ethanol(enantiomer #2) 300.07 301.1 1.63 56

4-(5-(1-hydroxy-1- (pyridin-4- yl)ethyl)thiazol-2- yl)benzonitrile307.08 308.5 1.57 57

1-(5-(1H-pyrazol-4- yl)oxazol-2-yl)-1- (pyridin-4- yl)propan-1-ol 270.11271.5 1.36 58

5-(5-(1-hydroxy-1- (pyridin-4- yl)ethyl)furan-2-yl)- 1-methylpyridin-2(1H)-one 296.12 297.1 0.92 59

5-(2-(4- fluorophenyl)thiazol- 5-yl)-6,7-dihydro- 5H-cyclopenta[c]pyridin- 5-ol 312.07 313.1 5.2 60

5-(5-(1-hydroxy-1- (pyridin-4- yl)ethyl)oxazol-2- yl)-1-methylpyridin-2(1H)-one 297.11 298.1 1.30 61

1-(5-(4- fluorophenyl)-1,3,4- thiadiazol-2-yl)-1- (pyridin-4-yl)ethanol301.07 302.1 1.99 62

1-(6′-(1-hydroxy-1- (pyridin-4-yl)ethyl)- [3,3′-bipyridin]-6-yl)pentan-1-one 361.18 362.2 2.42 63

1-(5-(4- fluorophenyl)iso- thiazol-3-yl)-1- (pyridin-4-yl)ethanol 300.07301.5 1.43 64

1-(pyridin-4-yl)-1- (2-(pyrimidin-5- yl)thiazol-5- yl)ethanol 284.07285.0 1.08 65

1-(2-(4- fluorophenyl)thiazol- 5-yl)-1-(pyridin-4- yl)ethyl acetate342.08 343.1 2.43 66

1-(2-(4- fluorophenyl)thiazol- 5-yl)-1-(pyridin-4- yl)ethyl propionate356.10 357.2 4.94 67

1-(2-(4- fluorophenyl)thiazol- 5-yl)-1-(pyridin-4- yl)ethyl butyrate370.12 371.2 5.31 68

1-(2-(4- fluorophenyl)thiazol- 5-yl)-1-(pyridin-4- yl)ethanamine 299.09300.1 4.26 69

N-(1-(2-(4- fluorophenyl)thiazol- 5-yl)-1-(pyridin-4- yl)ethyl)acetamide341.10 342.1 1.05

Examples 70-83

The following compounds are prepared using the procedures discussed inSchemes 1-19 and Examples 1-69 noted above:

a)4-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)thiazol-2-yl)-1H-pyrrole-2-carbonitrile

b)4-(5-(1-hydroxy-1-(pyridin-4-yl)propyl)thiazol-2-yl)-1H-pyrrole-2-carbonitrile

c)4-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)-1,3,4-thiadiazol-2-yl)-1H-pyrrole-2-carbonitrile

d)4-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)-1,2,4-oxadiazol-3-yl)-1H-pyrrole-2-carbonitrile

e)4-(5-(1-amino-1-(pyridin-4-yl)ethyl)thiazol-2-yl)-1H-pyrrole-2-carbonitrile

f) 1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanamine

g) 1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)propan-1-amine

h)1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-1-(pyridin-4-yl)ethanamine

i)1-(2-(3-chloro-4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanamine

j) 1-(5-(4-fluorophenyl)pyridin-2-yl)-1-(pyridin-4-yl)ethanamine

k)5-(5-(1-amino-1-(pyridin-4-yl)ethyl)thiophen-2-yl)-1-methylpyridin-2(1H)-one

l) 1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)-1-(pyridin-4-yl)propan-1-amine

m) 1-(2-(5-cyano-1H-pyrrol-3-yl)thiazol-5-yl)-1-(pyridin-4-yl)ethylacetate

n)N-(1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-1-(pyridin-4-yl)ethyl)acetamide

Example 84 CYP17 Inhibition Assay in Rat Testicular Microsomes (RatCYP17) or Yeast Microsome Overexpressing Human CYP17 A. Materials

1. NADPH (Sigma): A working stock was prepared by adding 25 μL of 6.5 mMNADPH in each tube. The final concentration of NADPH used in the assaywas 325 μM.2. Potassium Phosphate Buffer: One molar (1M) solutions of K₂HPO₄ andKH₂PO₄ were prepared. Eight mL of the 1 M KH₂PO₄ and 1.98 mL of the 1 MK₂HPO₄ were combined and the pH was adjusted to 7.4.3. ³H₃-17α-hydroxypregnenolone (American Radiolabeled Chemicals, Inc.,stock 1 μCi/μL): A 1:1 dilution of ³H₃-17α-hydroxypregnenolone inethanol was prepared by combining 100 μL ³H₃-17α-hydroxypregnenolone+100μL ethanol for one complete 96 well plate. For the reaction, 2 μL of thediluted ³H₃-17α-hydroxypregnenolone was added in each tube, i.e., 1μCi/reaction.4. Microsome Isolation Buffer: The microsome isolation buffer wasprepared by combining 250 mM Sucrose, 5 mM EDTA, 10 mM Tris HCl, 4 mMDTT, and adjusting to pH 7.4.5. TEG Buffer: The TEG buffer was prepared by combining 50 mM Tris HCl,1 mM EDTA, and 20% Glycerol.6. Rat Testicular Microsomes: Rat testis tissue was collected anddisrupted with 30 strokes of a glass homogenizer on ice with 250 μL ofmicrosome isolation buffer, followed by centrifugation at 10,000 g for10 minutes at 4° C. The supernatant was collected and centrifuged at100,000 g for 45 minutes at 4° C. The pellet was dissolved in TEG Bufferand the protein was quantified. The homogenized microsome samples werethen frozen at −80° C.7. Yeast Microsomes which overexpress the human CYP17 enzyme wereobtained from Premas Biotech, India.

B. Procedure

Potassium phosphate buffer (470 μL) was prepared as described above andwas added to each well of a deep well plate. The test compound wasdiluted using a TECAN liquid handler and 5 μL of diluted compound wastransferred to each well (96 deep well/1 mL). A solution (25 μL) of 6.5mM NADPH was added (final concentration of 325 μM in the assay).³H₃-17α-hydroxypregnenolone (2 μL of the working stock) was added toeach tube. The plates were then pre-incubated for 15 minutes at 37° C.Following the pre-incubation, either 5 μL rat testicular microsomes(150-160 μg) or 5 μL of yeast microsomes expressing human CYP17 (1.7pmol), was added. Incubation was at 37° C. for 60 minutes in thepresence of oxygen. The plates were then placed in ice and chloroform(500 μL) was added, mixed well and incubated at 4° C. for 20 minutes.The plates were then centrifuged at 1000 rpm for 15 minutes at 4° C.

A portion (300 μL) of the aqueous solution was collected and mixed witha 5% aqueous suspension of activated charcoal (300 μL). The plates werethen incubated at 4° C. for 30 minutes, after which the plates werecentrifuged at 1000 rpm for 15 minutes at 4° C. From this, 125 μL of theaqueous solution was collected and plated into a 96 well plate.Microscint™ 40 [125 μL, Perkin-Elmer; containing a mixture of a polymerbased on alkylphenolethoxylate (20-40%), diethanolamine-phosphoric acidester ammonium salt (10-20%), sodium dioctyl sulphosuccinate (2.5-10%),triethyl phosphate (2.5-10%), 3,6-dimethyl-4-octyne-3,6-diol (≦2.5%), apolymer based on nonylphenolethoxylate (≦2.5%), diisopropyl naphthaleneisomers (40-60%), 2,5-diphenyloxazole (≦2.5%), and9,10-dimethylanthracene] was added and mixed well. After 30 minutes ofincubation, the samples were analyzed with a MicroBeta® Triluxmicroplate liquid scintillation counter and luminometer (Perkin-Elmer).

Compounds of formula (I) caused inhibition of rat microsomal CYP17 andrecombinant human CYP17 enzyme activity as determined by these assays.Data are listed in Table 3.

Example 85 Cell-Based Human CYP17 Inhibition Assay A. Materials

1. H295R Adrenocortical Carcinoma Cells and Growth Media: The media forthe H295R Adrenocortical carcinoma cells [NCI-H295A, ATCC NumberCRL-2128, American Type Culture Collection, Manassas, Va., US] (500 mL)was a DMEM:F12 Mix 1:1 with 5% (2 mL) BD Nu Serum; 1% (5 mL) ITS+Premix[BD Biosciences] and 1% Penstrep.2. LNCap-CYP17 Cells and Growth Media: Full length hCYP17a1 gene (NCBIReference Sequence: NM_000102.3) was cloned in pcDNA3.1(+) vectorbetween HindIII and XhoI site. The pcDNA3.1(+) vector contains theNeomycin resistance gene and was used for selection of stable cell line.The hCYP17a1 containing pcDNA3.1(+) was transfected into LNCap cells tocreate the LNCap-CYP17 cell line. The media for the LNCaP-CYP17 cellswas RPMI 1640, 10% FBS, 1% PenStrep, Geneticin 400 μg/mL.

B. Procedure

The H295R cells or LNCaP-hCYP17 cells were subcultured and 30,000 cellsper well were seeded in a poly-d lysine plate and incubated overnight at37° C. The next day the media was removed and 200 μL of fresh media with³H₃-17α-hydroxy-pregnenolone (1:1000) was added. 50 μL of seriallydiluted compounds from a 5× plate (5 times the final desiredconcentration) was added. The working concentration range for active,new compounds started from a high concentration of 10 μM with 3-foldserial dilutions generating up to 10 concentrations. The serial dilutionin the 100× plate (in DMSO) and the stamping of a 5× plate (in media)from the 100× plate were carried out using a TECAN liquid handlingdevice.

The plates were incubated overnight (16 hours) at 37° C. After 16 hours,the media was removed (approximately 220 μL) and an equal amount ofchloroform was added, mixed and incubated for 30 minutes at 4 degrees.The plate was centrifuged at 4000 rpm for 15 minutes at 4° C., followingwhich the top aqueous layer was carefully removed and added into a newdeep well plate. An equal volume of activated 5% charcoal was added,mixed and incubated for 30 minutes at 4° C. The plate was thencentrifuged at 4000 rpm for 15 minutes at 4° C. and the top layercarefully separated, avoiding any charcoal contamination, and placed ina white, clear bottom plate (plate cat #3610, Corning Life Sciences). Anequal volume of Microscint™ 40 was added and mixed well. Following theincubation for 30 minutes, readings for the radiotracer were taken usinga Microbeta® trilux.

Compounds of formula (I) caused inhibition of human CYP17 enzymeactivity as determined by these cell assays. Data are listed in Table 3.

Example 86 Cell-Based Functional Assay for Testosterone Production

H295R cells (ATCC Number CRL-2128) were subcultured, seeded (30,000cells per well in a poly-d lysine plate) and left overnight at 37° C.The next day (after approximately 24 hours), the media were removed and200 μL fresh media were added. Then, 50 μL of serially diluted compoundswas added from a 5× plate. The serial dilution in the 100× plate (inDMSO) and the stamping of a 5× plate (in media) from the 100× plate werecarried out using a TECAN liquid handling device. The plate wasincubated at 37° C. for 72 hours. After incubation, the media wasremoved, diluted 5 to 10 times with calibration diluent RD5-48, and theassay performed as per manufacturer's protocol (Parameter TestosteroneAssay, Cat. No. KGE010, R&D systems;http://www.rndsystems.com/pdf/KGE010.pdf).

Compounds of formula (I) caused inhibition of testosterone production inH295R cells as determined by this assay. Data are listed in Table 3.

Example 87 In Vivo Inhibition of Testosterone Production

Male rats aged 8 to 10 weeks old were dosed orally with compounds at 10or 30 mg/kg. Blood samples were drawn at 0.5, 3, 8, and 24 hours andwere processed to plasma samples. Samples were analyzed for compoundlevels by LC-MS/MS method and for testosterone levels with an ELISAperformed as per manufacturer's protocol (Parameter Testosterone Assay,Cat. No. KGE010, R&D systems; http://www.rndsystems.com/pdf/KGE010.pdf).The serum testosterone level was calculated from standards usingGraphPad® Prism software and % inhibition at a given time was calculatedby comparing the testosterone level in vehicle control animals at thesame time of day.

Compounds of formula (I) decreased serum testosterone levels asdetermined by this assay protocol. For example, the compound of Example14 decreased serum testosterone levels 60-80% at 3-8 hours after a 30mg/kg oral dose compared to vehicle-dosed control animals sampled at thesame time of day. The compound of Example 7 decreased serum testosteronelevels 70-85% at 3-8 hours after a 10 mg/kg oral dose compared tovehicle-dosed control animals sampled at the same time of day. Thecompound of Example 17 decreased serum testosterone levels 30-60% at 3-8hours after a 30 mg/kg oral dose compared to vehicle-dosed controlanimals sampled at the same time of day. The dosing formulations usedwere 5% hydroxy propyl-β-cyclodextrin in 30 mM methane sulfonic acidsolution (v/v) for Example 7, and Tween-80™ reagent, 0.5% methylcellulose for Examples 14 and 17. In one study, the compounds ofExamples 17, 34 and 36 decreased serum testosterone levels about 85-95%at 3 hours after a 30 mg/kg oral dose compared to vehicle-dosed controlanimals sampled at the same time of day.

Example 88 In Vivo Reduction of Prostate and Seminal Vesicle Weights

Male rats aged 8 to 10 weeks old (5 animals per group) were dosed orallywith compounds once or twice a day at 12-hour intervals for 14 days. Onday 14 the animals were euthanized and organs were surgically removedfor wet weight determination including the prostate, seminal vesiclesand testes.

Compounds of formula (I) decreased prostate and seminal vesicle weightsas determined by this assay protocol. For example, the compounds ofExamples 7 and 9, when dosed at 10 mg/kg orally twice a day for 14 days,reduced prostate weights by 20 to 30% and reduced seminal vesicleweights by 30 to 50%. The compound of Example 7, when dosed at 30 mg/kgorally once a day for 14 days, reduced prostate weight by about 50% andseminal vesicle weights by about 60%. The dosing formulation used was 5%hydroxy propyl-β-cyclodextrin in 30 mM methane sulfonic acid solution(v/v). The compounds of Examples 17, 34 and 36, when dosed at 30 mg/kgorally twice a day for 14 days, reduced prostate weight by about 50% andseminal vesicle weights by about 50-70%.

TABLE 3 CYP17 CYP17 CYP17 CYP17 Testos- (rat testi- (human, (human(human terone cular yeast H295R LNCap- (human micro- micro- adrenalCYP17 H295R Ex. somes) somes) cells) cells) adrenal cells) 1 A C B C B 2A B B 3 B C B 4 A B A 5 A C 6 A B 7 A B B A 8 A C C B 9 A B A A 10 A C11 A C 12 A B 13 A C 14 A A 15 A C B 16 B B 17 A B A 18 A A 19 A A 20 C21 A C 22 C 23 A C 24 A B 25 A C 26 A B 27 A A 28 A A 29 A C 30 A B 31 BC 32 A B 33 A A 34 A A 35 A C 36 A A A 37 B B 38 A B 39 A B 40 A A 41 AA 42 A A 43 A A 44 A A 45 B C 46 A A 47 A A 48 A A 49 A C 50 A B 51 A A52 A A 53 B C 54 A A 55 A B 56 A B 57 B C 58 B C 59 B C 60 C C 61 A B 62B C 63 A A 64 A C 65 A 66 A 67 A 68 A B 69 B C Activities (nM): A: IC₅₀< 50; B: IC₅₀ = 50-200; C: IC₅₀ = 201-10000.

All publications cited in this specification and priority applications,including U.S. patent application Ser. No. 13/632,006, filed Sep. 30,2012, U.S. Provisional Patent Application No. 61/541,621 andInternational Patent Application No. PCT/US2012/57899, are incorporatedherein by reference. While the invention has been described withreference to particular embodiments, it will be appreciated thatmodifications can be made without departing from the spirit of theinvention. Such modifications are intended to fall within the scope ofthe appended claims.

1. A compound of formula (I) of the structure:

wherein: A is optionally substituted phenyl or optionally substitutedheteroaryl; B is optionally substituted heteroaryl; Q is O or NH; R′ is:(a) H, or C₁ to C₄ alkyl; or (b) two or three methylene fragments thatare joined to a carbon atom at the 3-position of the pyridine ring; or apharmaceutically acceptable salt or prodrug thereof. 2-4. (canceled) 5.The compound according to claim 1, wherein A is optionally substitutedpyridine. 6-14. (canceled)
 15. The compound according to claim 1,wherein B is an optionally substituted pyridine. 16-18. (canceled) 19.The compound according to claim 1, wherein B is of the structure:

wherein: X and Y are independently selected from the group consisting ofCR²³ and N; Z is NR²⁴, O or S; each R²³ is, independently, H, F, Cl,CH₃, CF₃ or CN; and R²⁴ is H or C₁ to C₄ alkyl.
 20. The compoundaccording to claim 19, wherein B is of the structure:


21. The compound according to claim 19, wherein B is:


22. The compound according to claim 21, wherein B is:


23. The compound according to claim 22, wherein B is:


24. The compound according to claim 19, wherein B is:


25. The compound according to claim 24, wherein B is:


26. (canceled)
 27. The compound according to claim 19, wherein B is:


28. (canceled)
 29. The compound according to claim 1, which is of theformula (I-A):

30-33. (canceled)
 34. The compound according to claim 1, in the form ofan acid salt.
 35. The compound according to claim 34, wherein said acidis selected from the group consisting of acetic, propionic, lactic,citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic,phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,trifluoroacetic, and camphorsulfonic.
 36. The compound according toclaim 1, which is:6′-(1-hydroxy-1-pyridin-4-ylethyl)-3,3′-bipyridine-6-carbonitrile;5-[5-(1-hydroxy-1-pyridin-4-yl-ethyl)thien-2-yl]-1-methyl-pyridin-2(1H)-one;(R)-5-[5-(1-Hydroxy-1-pyridin-4-yl-ethyl)-thiophen-2-yl]-1-methyl-1H-pyridin-2-one;(S)-5-[5-(1-Hydroxy-1-pyridin-4-yl-ethyl)-thiophen-2-yl]-1-methyl-1H-pyridin-2-one;1-[2-(1H-pyrazol-4-yl)-1,3-thiazol-5-yl]-1-(pyridin-4-yl)-propan-1-ol;(R)-1-[2-(1H-pyrazol-4-yl)-1,3-thiazol-5-yl]-1-(pyridin-4-yl)-propan-1-ol;(S)-1-[2-(1H-pyrazol-4-yl)-1,3-thiazol-5-yl]-1-(pyridin-4-yl)-propan-1-ol;1-[2-(6-fluoropyridin-3-yl)-1,3-thiazol-5-yl]-1-(pyridin-4-yl)-ethanol;4-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)thiazol-2-yl)-1H-pyrrole-2-carbonitrile;4-(5-(1-hydroxy-1-(pyridin-4-yl)propyl)thiazol-2-yl)-1H-pyrrole-2-carbonitrile;4-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)-1,3,4-thiadiazol-2-yl)-1H-pyrrole-2-carbonitrile;4-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)-1,2,4-oxadiazol-3-yl)-1H-pyrrole-2-carbonitrile;1-(5-(1H-pyrazol-4-yl)oxazol-2-yl)-1-(pyridin-4-yl)propan-1-ol;5-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)furan-2-yl)-1-methylpyridin-2(1H)-one;5-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)oxazol-2-yl)-1-methylpyridin-2(1H)-one;1-(6′-(1-hydroxy-1-(pyridin-4-yl)ethyl)-[3,3′-bipyridin]-6-yl)pentan-1-one;or 1-(pyridin-4-yl)-1-(2-(pyrimidin-5-yl)thiazol-5-yl)ethanol.
 37. Thecompound according to claim 1, which is:4-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)thiazol-2-yl)-1H-pyrrole-2-carbonitrile;4-(5-(1-hydroxy-1-(pyridin-4-yl)propyl)thiazol-2-yl)-1H-pyrrole-2-carbonitrile;4-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)-1,3,4-thiadiazol-2-yl)-1H-pyrrole-2-carbonitrile;4-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)-1,2,4-oxadiazol-3-yl)-1H-pyrrole-2-carbonitrile;4-(5-(1-amino-1-(pyridin-4-yl)ethyl)thiazol-2-yl)-1H-pyrrole-2-carbonitrile;5-(5-(1-amino-1-(pyridin-4-yl)ethyl)thiophen-2-yl)-1-methylpyridin-2(1H)-one;1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)-1-(pyridin-4-yl)propan-1-amine; or1-(2-(5-cyano-1H-pyrrol-3-yl)thiazol-5-yl)-1-(pyridin-4-yl)ethylacetate.
 38. The compound according to claim 1, wherein thepharmaceutically acceptable salt is the hydrochloride, 4-methylbenzenesulfonic acid, benzene sulfonic acid, methanesulfonic acid, sulfuricacid or nitric acid salt. 39-40. (canceled)
 41. A method for inhibitingCYP17, said method comprising administering a therapeutically effectiveamount of a compound of claim 1 to a patient in need thereof. 42-43.(canceled)
 44. A method of treating cancer in a patient, said methodcomprising administering a compound of claim 1 to said patient, whereinsaid cancer is prostate cancer. 45-46. (canceled)